. Author manuscript; available in PMC: 2023 Nov 1.

Published in final edited form as: Semin Cancer Biol. 2021 Dec 27;86(Pt 3):914–930. doi: 10.1016/j.semcancer.2021.12.009

Rethinking the Chemokine Cascade in Brain Metastasis: Preventive and Therapeutic Implications

Shailendra Kumar Maurya ^a, Parvez Khan ^a, Asad Ur Rehman ^a, Ranjana K Kanchan ^a, Naveenkumar Perumal ^a, Sidharth Mahapatra ^a,^b,^e, Hitendra S Chand ^c, Juan A Santamaria-Barria ^d, Surinder K Batra ^a,^e,^f, Mohd Wasim Nasser ^a,^e,^*

PMCID: PMC9234104 NIHMSID: NIHMS1768291 PMID: 34968667

Abstract

Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10–40% of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.

Keywords: Chemokines, Brain Metastasis, Heterogeneity, Immune cells, Brain microenvironment

1. Introduction

Brain metastasis (BrM) is the process of spreading tumor cells to the brain from the primary malignancy, causing neurological dysfunction and greatly affecting overall survival (OS), with an incidence of 10–40 % in all cancer patients [1]. The OS of brain metastatic patients is poor (4 to 16 months) and depends on the primary tumor of origin [2]. BrM occurs in the primary malignancies, including lung (40–50%), breast (15–30%), melanoma (5–20%), colon (3–8%), and renal (2–4%) cancer patients (Fig.1) [3–6]. During BrM, circulating tumor cells (CTC) disseminate to different body parts, but brain seeding is a late event and 10 times more rapid than primary brain or central nervous system (CNS) malignancy [7]. Due to the blood-brain barrier (BBB), brain remains a ‘sanctuary’, that has tight vascular junctions and regulates systemic transport, constituting a major hurdle for the successful penetration of therapeutic agents to the brain [8, 9]. Although the advancement in early diagnostics and cancer treatments has improved the survival of cancer patients, it also has led to a rise in BrM cases. Cancer cells opt for the most common hematogenous passage en route to the brain and neuroinflammatory cascade aids in establishing a premetastatic niche that helps propel cancer cells to the brain [8, 10]. When reaching the brain milieu, cancer cells survival depends on crosstalk with neuronal cells, including endothelial cells, microglia and astrocytes. It is heavily influenced and regulated by cytokines/chemokines [11].

Figure 1: — The red and brown nodes depict cancer progression and metastasis from the primary lung, breast, melanoma, renal and colorectal cancers. Metastatic dissemination to the brain from the primary tumors is regulated through systemic circulatory routes.

Chemokines, small chemotactic secretory proteins, are known to regulate lymphoid tissue development and immune cell transport[12]. They are divided into four different categories such as 27 CC-, 17 CXC-, 2 XC-, and 1 CX3C chemokine, based on two first cysteine (C) residues present in protein sequence and where X serves as an arbitrary amino acid. These chemokines function by binding to their cognate receptors CR, CCR, CXCR, and CX3CR, forming a diverse class within the G-protein-coupled receptors (GPCR) [13]. Chemokines via innate or acquired immune responses regulate leukocyte migration by enlisting specific lymphoid cells to certain tissues. Other cell types can also capitalize on chemokine signaling by expressing the appropriate receptors. The chemokine-regulated pathways can be hijacked by metastatic tumor cells to aid in migration to distant sites [14]. Similar to leukocyte migration, cancer cell metastasis breaches vasculature barriers, enters blood circulation and extravasates at locations in organ-specific manner. As chemokines and their receptors modulate leukocyte trafficking, they can also initiate and regulate tumor cell migration and metastasis [14].

Chemokines including their receptors are critical in establishing metastatic heterogeneity and developing metastatic niches [15]. These chemokine axes at metastatic niches support the growth of heterogeneous tumors, promote the seeding of metastatic clones in the nascent microenvironment that recapitulates the heterogeneous nature of metastasis [15]. Heterogeneity induced by chemokines in cancer cells at the primary locations, further aids the higher incidences of metastasis to the brain. Tumor heterogeneity includes different characteristics such as differential cell growth, cell surface marker expression, antigenicity-immunogenicity, angiogenic, invasive, metastatic potential, and therapy response [16]. In addition, CTCs are genetically and metabolically heterogeneous, and they can metastasize to various organs, including the brain. Inter-metastatic heterogeneity occurs in BrM in the form of subtype switching and genomic alterations at the metastatic lesions relative to primary malignancies [17–19]. Additionally, the vessel microarchitecture has also been different in the brain metastatic lesions than their primary counterpart [20]. Such heterogeneous nature of specific cancers and their BrM is the key reasons for therapy failure. The brain has a unique microenvironment that contains various cells such as endothelial, myeloid, astrocytes, fibroblasts, neurons, and their crosstalk with metastatic cancer cells can fuel BrM [21]. Cancer-specific differential expression of chemokines and their receptors modulate downstream chemokine signaling [14]. In this review, we explore tumor heterogeneity to understand TME, along with immune cells in the regulation of chemokine signaling. Here we also discuss the role of different chemokines and how these chemokines promote BrM. Considering the lethality associated with BrM, this will help us understand and eventually could lead to develop novel therapeutics to mitigate dismal outcomes in patients with BrM.

2. Chemokines in Brain Metastasis

The biochemical, molecular, and phenotypic features of CTCs are controlled by a combination of different chemokine pathways [22]. The expression of discrete chemokines in the CTCs lead to site-specific metastasis. They often restrict the tumor adhesion on the vessel walls and promote extravasation into the target tissue [10]. Chemokines are usually categorized into inflammatory and homeostatic groups, and their binding to receptors is often associated with conformational changes and activating different signaling pathways. The abnormal activation of such chemokine signaling leads to altered expression of transcription factors along with oncogene activation and tumor suppressor genes inactivation [14, 23]. When these CTCs reach the brain, chemokines, and their receptors crosstalk with the brain microenvironment, leading to remodeling of the metastatic site, which attracts cells of immune origin and causes extracellular matrix (ECM) degradation. The basement membrane and modification of adhesion proteins are also modulated in the process and characterized by anatomy, cell types, immune and local metabolic transport [5, 24]. At the brain metastatic niche, chemokines, cytokines, angiogenic growth factors, and signaling molecules interact with other cell types and provide the growth signals for recruiting tumor cells [25]. Recent advancements in technology like single cell RNA sequencing (scRNA-Seq) have enhanced our ability to map the chemokine landscape of the metastatic brain microenvironment [26, 27]. Chemokines along with their receptors are the key players in establishing metastatic heterogeneity and niche [15]. Due to chemokine axes, metastatic niches at the different parts of the body that support the heterogeneous tumor growth may indirectly promote the seeding of metastatic clones in the newly formed microenvironment that represents the heterogeneous metastases [15].

Tumor heterogeneity is further aided by cancer stem cells (CSCs) or tumor-initiating cells. It has been shown that CSCs (CD133+/CXCR4+) are vital for pancreatic cancer metastasis [28]. In addition, higher chemokine receptors expressing Breast cancer (BC) cells show increased metastatic potential compared to low receptor levels [29, 30]. The CCL19 chemokine has been shown to induce heterogeneity via modulating the BC microenvironment [31]. Instead of attracting the leukocytes during cancer progression, these chemokines assist the inflammatory and immune-suppressive myeloid cells in assisting tumor survival, proliferation, and successful establishment of metastasis [32, 33]. Chemokines and their receptors may play a crucial role in organ-specific metastasis via escaping tumor immune surveillance. CCR7 and CCR10 promote melanoma metastasis, while CXCR4 expression leads to establishing brain metastasis [34, 35]. In addition to the tumor-promoting role, some chemokines have antitumor/anti-metastatic activities [32].

3. Chemokines and Tumor Microenvironment:

Cells secrete several chemokines for remodeling of TME through attracting distinct immune cell types towards site at the primary tumor for promoting cancer growth [36]. The TME of solid tumors consists of heterogeneous tumor cell types, tissue-resident cell types, including stromal and immune cell types [37–43]. These populations can vary inter and intra tumor heterogeneity leading to prominent disease diversity, thus complicating treatment [38]. These subpopulations of tumor cells express different surface receptors, like lectins, hormones, specialized biosynthetic enzymes, and metabolic characteristics, leading to a staggering response for drug sensitivity among different cell populations, both in primary and metastatic tumors [15, 44].

BrM establishes the molecular interaction between metastatic cancer cells and the surrounding brain microenvironment, such as endothelial cells, fibroblasts, pericytes, immune and brain cells [45, 46]. TME regulates dynamic signaling pathways like chemokines, inflammatory cytokines, and growth signaling for tissue remodeling [47]. These interactions alter the cell features at the phenotypic and genotypic levels, revealing more complex heterogeneity [48]. Altogether, the TME regulates abnormal tissue function and develops more advanced or refractory malignancies [49]. The critical features that differentiate the brain from other tissues include unique extracellular matrix (ECM) compositions, cell types, and a great BBB protecting the brain from inflammation. Thus, the brain is considered a privileged immune organ, protected from immune cells infiltration for various neuropathological reasons [46, 50–53]. For instance, the activated immune cells release different cytokines and chemokines that could be cytotoxic to the neurons and other brain cells [46, 50]. This discrete brain microenvironment is extended to brain cells, structural composition, immune responses, blood current, accessibility of oxygen, and nutrient [54–57]. Such properties pose a unique challenge to metastatic tumor cells and help in exploiting the neuroprotective environment that eventually develops therapy resistance [58]. The brain TME is a complex and potent network of tumor cells, stroma tissue like different stromal cells, cytokines, vascular tissue, infiltrating immune cells, and the surrounding secreted products of these cells [59, 60]. These components, viz ECM components, cytokines, chemokines, growth factors, antibodies, proteases, different enzymes, and various metabolites, are released by cancerous and non-cancerous cells [60]. With these secretory components, cells, and surrounding environment crosstalk to each other and regulates the homeostasis and evolution of TME [61].

3.1. Chemokines from Tumor Stroma

TME plays a crucial role in modulating metastasis through heterogeneity and acquiring resistance to therapy [45, 62]. Besides cancer cells, TME consists of collagen, proteoglycans, laminin, fibronectin, and stromal cells [63]. In TME, stromal cells interacts with cancer cells to regulate cancer initiation, progression, metastasis, and heterogeneity that modulates drug response which subsequently affects disease prognosis [64]. Stromal cells are responsible for the dissemination of cancer cells via ECM remodeling, invasion/migration, intravasation, persistence in blood circulation, extravasation, and growth at detached locations [65]. The stroma induces initiation of epithelial-mesenchymal transition (EMT) in tumor cells leading a highly aggressive phenotype for remodeling and metastasis [62, 66]. In brain tumors, the origin of primary and metastatic cancer is entirely different, but they share a similar microenvironment that affects cancer cells’ endurance [67]. The brain environment is regulated by stromal cells, including adipocytes, mesenchymal stem cells (MSCs), fibroblasts, pericytes, astrocytes, microglia, endothelial and immune cells. The stromal or ECM components regulate cancer pathogenesis, heterogeneity, and treatment outcome [46, 67, 68].

3.1.1. Blood-Brain Barrier

Due to a unique feature of brain anatomy, BBB separates brain from the systemic blood circulation [69]. BBB restricts the cells’ entry into the brain by physical obstructions. The primary function of BBB is to maintain the homeostatic environment needed for the normal functioning of the brain, thereby restricting the entry of toxins and pathogens [70]. BBB forms electrical resistance via tight junctions to prevent the free access of charged molecules, while pericytes and supporting endothelial cells promote its junctional integrity in a P2RY12 dependent axis [71]. Tumor cells first arrive at the brain vasculature; they get arrested in the blood vessels before the extravasation [58]. They extravasate into the brain either through paracellular (through the tight junctions between cells) or transcellular (via endothelial cells) manner (Fig.2) [58, 72]. The immune cell extravasation follows transcellular migration, while BrM is associated with paracellular migration [72]. The BBB can be weakened by cancer cells’ secretory factors such as inflammatory mediators (cytokines and chemokines), transforming growth factor–β (TGF-β), vascular endothelial growth factor (VEGF), essential basic fibroblast growth factor (bFGF), and prostaglandin-endoperoxide synthase-2 or cyclooxygenase-2 (COX2) [73–76]. Cancer cells also secrete different proteases (e.g., matrix metalloproteinases (MMPs) to disrupt the basement membrane for efficient metastasis to the brain [74, 77]. Following the entry into the brain, the cancer cells survive in the brain’s unique nutrient environment [58]. Neuron cells grow near the capillary that provides adequate oxygen for mitochondrial respiration, so the cancer cells in the brain exploit such phenotypic features, grow near the blood vessel, and contact it after extravasation [78]. This contact seems important as cancer cells co-opted with endothelial cells to remodel vasculature for efficient metastasis and angiogenesis [79].

Figure 2: — During brain metastasis, cancer cells interact with the tumor microenvironment at the primary site to promote cell motility/invasion via clearance of the extracellular matrix. At this stage, tumor cells disseminated from the primary sites and invade into surrounding areas, blood vessels, and lymph nodes i.e., intravasation. Tumor cells enter into the circulation, following the process of extravasation; these cells adhere to the brain microvasculature and finally reach the brain environment. Cancer cells remain at dormancy for a longer time, and some cancer cells start interacting with the brain microenvironment that allow them to establish neuroinflammatory cascades and neovascularization. In the brain, cancer cells start growing at the junction between grey and white matter and the watershed area between vascular territories.

3.1.2. Astrocytes

In the brain, cancer cells get exposed to reactive astrocytes that work as the first line of defense, [4] decreasing metastasis-initiating cells through activated plasmin, suggesting inefficient colonization of cancer cells [79, 80]. Interestingly, some cancer cells (lung and breast) evade this response by expressing plasminogen activator (PA) inhibitory serpins, like neuroserpin and serpin B2 to block plasmin activation [80], suggesting that targeting serpins may be useful for enhancing brain defenses against BrM. In the brain perivascular niche, the surviving cancer cells stay along with the neural stem cells (NSCs) that provide access to nutrients/oxygen supply through basal-lamina capillaries and endothelial-angiocrine factors [4]. Without angiogenesis, the interaction of cancer cells with the vasculature niche is called vascular co-option [80, 81]. This vascular co-option has been confirmed in experimental and clinical settings of melanoma, breast and lung cancers [79, 80, 82–85]. The β1-integrin and L1CAM regulate the entire vascular co-option process during the initiation of BrM [80, 86]. The metastasis initiating cells start proliferation and establish micro-metastasis using various experimental models [80, 86]. However, a tiny number of these micro-metastases will reach a clinically approved detectable size [87]. Several studies have shown that the differential growth of these metastases is supported by the brain-reactive astrocytes [88, 89]. A study reported that protocadherin 7 (PCDH7) plays a key interacting role between cancer cells and reactive astrocytes [88]. This hemophilic interaction provoked Connexin 43 (CX43) dependent gap junction, trafficking of ions, and secondary messenger [90–92]. This heterotypic interaction between cells and proteins enhances resistance to chemotherapy and tumor growth reducing intracellular Ca²⁺ level [90] and initiating Stat1-p65 signaling [88]. Thus, systemic therapy experiences compound barriers for simple drug penetration and thus attenuate the efficacy of the drugs within the brain [93, 94]. In addition, the reactive astrocytes also secrete different chemokines and extracellular vesicles to influence brain-metastatic progression [4]. The exosomes secreted by astrocytes downregulate PTEN by miR-19a to enhance the aggressiveness of BC cells [95]. Interestingly, extracellular vesicles (EVs) released by activated astrocytes influx into circulation to facilitate the attraction of the leukocytes and CTC into the inflammatory brain microenvironment [96] [97]. Metastasis-associated astrocytes activate the CXCL10-CXCR3 axis to recruit melanoma CTC to the brain and enhance brain metastasis [98, 99]. These findings further establish the functional significance of reactive astrocytes in modulating the brain microenvironment that favors brain metastasis.

3.1.3. Microglial cells

Bone marrow-derived macrophages (BMDMs) and microglia (tissue-resident) are the diverse macrophage populations present in the brain [46]. The microglia originate from progenitor cells embryonic yolk sac, and their maintenance occurs through cellular longevity and proliferation [46]. These macrophages are largely stable populations in the adult CNS that matures during embryonic development [46]. The integrity of BBB is compromised and permissive to monocytes during tumor progression. These circulating monocytes reach the brain parenchyma during pathological conditions and produce BMDMs [46]. Microglia and BMDMs play differential role in the brain and are currently under active investigation for their role in metastasis [46, 100–102]. During BrM, pre-metastatic niche (PMN) supports tumor growth, and the interaction between disseminated cancer cell (DCC) and PMN components is essential for the process [95]. The metastatic niche comprises heterogeneous cellular and acellular components and directly controls metastatic disease progression [95]. CNS myeloid and bone marrow (BM) myeloid cells significantly regulate brain immunity [95]. However, Guldner et. al. using scRNA-Seq have demonstrated that BM-myeloid plays a less defined role in BrM, whereas CNS-myeloid cells promote BrM through downregulating the CX3CR1 axis and CXCL10 upregulation. This CXCL10, in turn, recruits VISTAhiPD-L1, and inhibition of this axis leads to decreased immune suppression [27].

During metastasis, the metastatic cells gain some additional properties, that make them to be neoplastic. Several intrinsic characteristics of the neoplastic cells regulate how cancerous cells react with stroma and promote angiogenesis, inflammation, immune invasion, resistance to growth inhibition, and relative autonomy [65]. As a result, these cells pierce the BBB and start unleashing various chemokines to alter the brain microenvironment for survival [103]. One of the critical defense players in the brain is microglia, which is polarized M2 from M1 phenotype in the presence of tumor cells and, thus, promotes BrM. Wu et al. have shown that nicotine via its nACh receptor, present in microglia, induces CCL20 skewing microglia in M2 phenotype for promoting lung cancer BrM [104]. Metastasis-promoting functions of microglia have been reported using a brain-slice co-culture model and found associated with high CXCR4 and upregulated PI3K signaling [105, 106].

Further, the activation of chemokines (CXCL9, CXCL10, and CXCL11) enhances immune cells recruitments and unleashes immunotherapy responses via T helper type 1 (Th1) activated immunity and mammalian target of rapamycin (mTOR) signaling in the TME. [107] [108–110]. Stromal components also participate by inhibiting the antitumor immune response. In TME, the stromal component provides a physical barrier to the entry of immune cells and actively obstructs antigen presentation to T–cells that suppress the immune system [111]. Altogether, these studies suggest that chemokines regulate M2 microglia and thus play an essential role in establishing BrM.

3.2.1. Cancer-Associated Fibroblasts (CAFs)

Fibroblasts co-exist with other stromal cells in the TME. The continuous crosstalk of these essential residents of TME with tumor cells acquires an activated state via chemokines and growth factors mediated signaling. These hyperactivated fibroblast cells, Cancer-Associated Fibroblasts (CAFs), are highly heterogeneous in origin, phenotype, function, and constitute principle TME component [112, 113]. Furthermore, multiple factors modulate CAFs with the help of a different type of communication. The biochemical factors that regulate CAF’s transformation are created by CAFs for metastasis viz: VEGF, FGF, TGF-β1, CXCL12, PDGF, and IL-6, etc. [62, 114]. The CAF also remodels the ECM and tumor vasculature by ECM and MMPs proteins. CAFs also release TGF-β, IL-1, IL-6, chemokines CXCL8, CXCL12, CXCL14, CCL2, CCL5, and CCL7 to promote tumor progression, angiogenesis, and metastasis [115, 116] [117]. In addition, CAFs promote BrM of breast cancer by producing CXCL12 and CXCL16 chemokines [118]. Hepatocellular carcinoma (HCC) cells secrete high levels of CXCL16 and CC chemokines CCL2, CCL5, and CCL7. Using a pre-clinical mouse model, CAFs are shown to enhance migration and invasion to the lung, brain, and bone. Interestingly, CCL2 and CCL5 promote migration via hedgehog (Hh) activation, whereas CXCL16 and CCL7 promote migration and invasion through enhancing TGF-β activity in HCC cells [119].

Of interest, CAFs are associated with ECM remodeling and work as secretome for various chemokines, including CXCL12. The CAFs may help cancer cells to achieve a highly aggressive phenotype and establish distant metastasis. This can be understood by an elegant study that ablates CXCL12 from stromal fibroblasts using a fibroblast specific Cre. When these mice were crossed with MMTV-PyMT mice, they showed a delay in tumor growth and diminished pulmonary metastasis, suggesting that deleting CXCL12 in the mammary fibroblasts is enough to block metastasis to lung via inhibiting intravasation process of breast cancer cells [120]. CAFs enhance tumor growth, angiogenesis, and metastasis via degrading ECM through secreting factors and MMPs [111]. Mesenchymal stromal cells produce TGF-β and T cell ligands in TME that diminish the immune response and hamper T-cell contact with tumor cells [111]. Thus, targeting CAFs in TME will be an excellent therapeutic strategy for cancer or BrM treatment [21].

3.2.2. Mesenchymal stromal cells (MSCs)

Multipotent stem cells are known as MSCs. These cells are present as organ pericytes that initiate tumorigenic processes by regulating angiogenesis and metastasis [121]. These cells are essential in promoting migration, angiogenesis, acquiring drug resistance, stemness, and supporting immune responses of the cancer cells through cytokines and TGF-β [122–128]. The activation of MSCs by TNF-α promotes lung cancer metastasis by CCL5 and CCL2. This activation promotes neutrophil recruitment to the tumor to MSCs regulated metastasis [129]. MSCs induce CXCR4, CCR2, and CCR7 receptors on the surface of cancer cells that help in homing of the tumor cells [130]. Further, these MSCs release MMP2 for transmigration across the endothelial cells and promote the process of homing [131].

3.3. Chemokines from Immune Cells

The TME consists of specific immune cells, such as lymphocytes, neutrophils, eosinophils, macrophages and myeloid-derived suppressor cells (MDSCs). These heterogeneous TME immune cells have been shown to regulate the antitumor responses [40, 132]. A study on melanoma patients showed significant heterogeneity exists in immune cell infiltrates in TME [132]. These heterogeneous immune cells of leukocyte subsets, including myeloid and lymphoid lineages, regulate the expression of essential chemokines and proangiogenic mediators that diminish apoptosis and favorably enhance tumor growth via autocrine and paracrine signaling [133]. During this entire process, the immune cell behavior and mechanism of action are modified to promote the cancer cell growth and migration in the TME [40, 134]. The most common factors involved in such regulation are tumor necrosis factor-α (TNF-α), TGF-β, fibroblast growth factors (FGFs), interleukins (IL), epidermal growth factor (EGF), histamine, heparin, and chemokines [135]. Moreover, they also release some proteases like serine, cysteine, and metalloproteases, which are required for the ECM structure and function. This modification induces signaling for uncontrolled growth or proliferation of the cells [40].

The histological analysis of the various solid tumor patients represents a phenotype of T cell infiltrates that exist in TME. In breast cancer, cytotoxic Th1 cells are activated in both tumors and peritumoral stroma [136]. During T cell infiltration in TME, the CAFs promote the accumulation of macrophages. The interaction of these tumor-associated macrophages (TAM) with CAFs proclaims the recruitment of the monocyte through CCL2 and CXCL12, and also educates monocytes to M2 macrophages, therefore, exerting immune-suppressive roles in prostate and breast cancers [137, 138]. The crosstalk among tumor cells, CAFs, and M2 macrophages further intensify the tumor cell dissemination via primary malignancy. The decrease in estrogen receptor (ER) expression in prostate cancer cells also promote migration and invasion by increasing CCL5 and IL-6 expression in M2 macrophages and CAFs [139] (Fig.3).

Figure 3: — The multiple roles of chemokines and their receptors in the regulation of immune cells recruitment influence the growth of cancer cells at primary as well as brain metastatic sites. Chemokines regulate immune cell trafficking via their respective receptor at the primary tumor site and promote the growth and proliferation of cancer cells in the presence of stromal cells in the TME. The chemokines released from distant sites direct disseminated cancer cells to establish brain metastasis.

Chronic inflammation with the support of the environment potentiates cancer growth and metastasis in solid tumors [140]. The activation of transcriptional factors induces inflammation and remodeling of the TME. Likewise, the Myc family proteins recruit mast cells in TME to induce inflammation, angiogenesis and finally assist tumor cell dispersion. Ras protein also contributes to inflammation and neovascularization by increasing the expression of CXCL8/IL-8 signaling [141]. In TME, the inflammatory cells take over immune responses (both innate and adaptive to boost tumor growth by blocking immune effector cell recruitment, survival, and function [142]. Inflammatory cells together with other tumor associated stromal and immune cells regulate the immune suppressive function by releasing inflammatory chemokines CXCL5, CXCL12, CCL2, CCL20, and cytokines IL-23, IL-10, IL-8, IL-6, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, and TGF-β (Fig.3) [140]. A key anti-inflammatory cytokine IL-10 inhibits dendritic cells activation and differentiation and thus blunt the effector functions of CD8+ T cells. In addition, by recruiting the regulatory T cells (Treg), tumor cells regulate innate and adaptive immune responses. The antitumor immune responses are mediated by the release of IL-10 from the myeloid cells to promote Treg functions and inhibit NK and cytotoxic T cell responses via release of arginase, nitric oxide species (NOS) and reactive oxygen species (ROS) [141]. Furthermore, tumors employ evasive immune mechanisms via activation of transcription factors STAT3 and NF-κB and suppression of antitumor immune response and DC maturation. Immune cells guide various steps for the successful establishment of the metastatic cascade, such as circulating monocyte helps renal cancer cell invasion and angiogenesis [143]. The release of TGFβ and IL-10 from tumor cells educates immune infiltrates (macrophages and neutrophils) towards tumor-promoting phenotype [144]. The chemokines released by the cancerous and non-cancerous cells are firmly and causatively linked with tumor progression. These released chemokines work as a chemoattractant to attract the leukocyte, immunosuppressive myeloid cells in the tumor, promoting tumor progression and metastasis.

3.4. Role of Chemokine in the TME

Chemokines are secreted by a heterogeneous population of stromal cells, such as fibroblasts, endothelial cells, and immune cells [30, 145]. The whole immune system directly or indirectly depends on the cytokines and chemokines to coordinate their function and response towards oncogenesis [30, 146]. During the inflammation heterogeneous population of tumor cells and stromal cells produce different chemokines [147]. These chemokines convey the biological information of cancerous cells to other surrounding cells and play critical role in regulating tumorigenesis and immunomodulation [118, 148, 149]. Pre-clinical studies utilizing mouse model systems strongly suggests that chemokine cascade crosstalk with cancer cells enhances metastasis [30, 150]. The interaction of chemokines with their receptors is one of the causes of the disease progression at the primary site and advancement of the metastasis by inducing angiogenesis [151]. For instance, fibroblasts derived from BrM show higher expression of CXCL12/CXCL16 as compared to primary breast cancer. Such high expression of these chemokines promotes cancer metastasis (Table 1) [118].

Table 1.

Role of different chemokines in cancer metastasis.

Chemokines	Chemokine Receptors	Type of Cancer	Function
CXCL12	CXCR4	Breast cancer [12, 246] Prostate cancer [158, 247–249]	Recruitment of B cells and pDCs; and Treg cells into the bone marrow, Promotes proliferation angiogenesis and survival; drives invasion and brain metastasis;
CXCL6, CXCL8	CXCR1	Breast cancer [250] Prostate cancer [250] Lung cancer [250, 251] Melanoma [250, 252]	Recruitment of granulocytic MDSCs and neutrophils; Promotes invasion, migration angiogenesis and stemness; Resistance to hypoxia, apoptosis; and premature senescence;
CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8	CXCR2	Lung cancer [253] Pancreatic cancer [253] Prostate cancer [253] Melanoma [254–256] Breast cancer [135]	Recruitment of MDSCs and neutrophils, Promotes migration; invasion; premature senescence and angiogenesis
CXCL9, CXCL10 CXCL11, CXCL4L1	CXCR3	Melanoma [253, 257] Breast cancer [258]	Recruitment of NK Cells, and T cells Angiogenesis inhibitors
CXCL13	CXCR5	Pancreatic cancer [253, 259] Colon cancer [253, 259]	Invasion and metastasis, growth and proliferation
CCL3, CCL4, CCL5, CCL7, CCL14, CCL15, CCL16, CCL23	CCR1	Breast cancer [253] Lung cancer [253] Prostate cancer [253] Breast cancer [260]	Recruitment of monocytes, macrophages, TAM and DC, Promotes angiogenesis invasion, extravasation and metastasis,
CCL2, CCL7, CCL8, CCL12, CCL13	CCR2	Breast cancer [253] Glioma [253] Lung cancer [253] Melanoma [253] Prostate cancer [253]	Recruitment of monocytes, NKT cells, TAM, fibroblast and monocytic MDSCs Promotes proliferation of tumor cells, stemness, survival, vascularization, extravasation and metastasis
CCL5, CCL7, CCL11, CCL13, CCL15, CCL24, CCL26, CCL28	CCR3	Breast cancer [253]	Recruitment of monocytes and Macrophages, Promotes cancer invasion, extravasation, and metastasis
CCL2, CCL3, CCL5, CCL17, CCL22	CCR4	Breast cancer [261] Melanoma [195]	Recruitment of T-cell, monocytes and macrophages, Promotes cancer invasion, extravasation, and metastasis
CCL3, CCL4, CCL5 CCL8	CCR5	Breast cancer [253, 262] Lung cancer [253] Pancreatic cancer [253] Prostate cancer [253]	Recruitment of monocytes and macrophages, Promotes cancer growth, invasion, extravasation, metastasis
CCL20	CCR6	Breast cancer [253, 263]	Proliferation recruitment, invasion, and metastasis, of DC
CCL19, CCL21	CCR7	Breast cancer [12] Lung cancer [12, 264]	Invasion and metastasis, survival
CCL25	CCR9	Melanoma [265] Prostate cancer [266]	Invasion and metastasis, survival
CCL27, CCL28	CCR10	Melanoma [267]	Invasion and metastasis, growth, survival
CX3CL1	CX3CR1	Pancreatic cancer [268–270] Prostate cancer [271] Breast cancer [272]	Invasion and metastasis, survival
CXCL11, CXCL12	ACKR3 (CXCR7)	Breast cancer [273] Prostate cancer [165]	Recruitment of B cells and pDCs; and Treg cells into the bone marrow, Promotes proliferation, invasion, metastasis; stemness, angiogenesis, and survival

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3.4.1. CXCL12-CXCR4 axis

Metastatic tumors express higher levels of CXCL12 relative to primary tumors or normal breast tissues [118]. The function of CXCL12 is to attract cancer cells derived from primary site through CXCR4 to the metastatic destination and support their growth in an autocrine manner [26]. The CXCL12/CXCR4 axis establishes communication of cancer cells with their surrounding stroma [152], via immune trafficking and metastasis [153]. The expression of CXCL12 and CXCR4 is associated with CSC properties, which are crucial for breast cancer BrM [153]. The subventricular zone of brain secretes CXCL12 for the attraction of CXCR4 expressing CSCs. The binding of CXCL12 to CXCR4 promotes tumor angiogenesis, immunosuppression, and remodeling of microenvironment. The CXCL12/CXCR4 axis induces a PMN formation in the brain [154], substantiating the importance of CXCL12 in forming the PMN [155]. During early stages of tumor progression, CXCR4 expression is increased, and CXCR4 activation promotes the growth and metastasis of various tumors [156]. Blocking the CXCL12/CXCR4 axis substantially reduces cancer cell migration towards the brain, implicating its role in brain metastasis and can be an excellent therapeutic choice [118].

During tumorigenesis, the expression of CXCL12 increases inside the tumor and nearby tumor vessels, whereas the CXCR4 receptor is present in tumor and metastatic cells. The CXCL12/CXCR4 axis is essential for CNS embryonic development and is also present in the adult brain. CXCL12 expression increases in the endothelial cells during BrM and promotes cancerous cells to cross the BBB [26]. The CXCL12/CXCR4 axis promotes migration through activation of IKKa/b, NF-κB, and ERK, which activates integrins (ITGB1 and ITGB3) in lung cancer cells [157]. It also supports the growth of tumor cells at distant and less fortunate sites [156, 158]. This axis is majorly responsible for breast cancer BrM and works as a predictive factor for worse metastatic tumors [159, 160].

3.4.2. CXCL12-CXCR7 axis

The CXC chemokine receptor 7 (CXCR7) interacts with CXCL11 and CXCL12 [161], and generally present on human endothelial cells of the colon, small intestine, testis, and brain. Enhanced expression of CXCR7/CXCR4 in TME is responsible for poor prognosis [162]. CXCR7 interacts with CXCR4 and forms a heterodimer to regulate calcium signaling by rearranging the CXCR4/GPCR complex [163]. These interactions affect cell survival, proliferation, and metastasis [163].

CXCR7 works as a scavenger for its ligand CXCL12, disrupting the CXCL12 gradient and modulating CXCR4 signaling [164]. Together with CXCR4, it regulates cell homing, interneuron migration and increases β-arrestin recruitment. Moreover, it upregulates MAPK, ERK, and TP53 signaling and promotes cell proliferation and survival [163]. In vitro studies show that co-expression of CXCR7 with CXCR4 increases cell migration, proliferation, and regulates angiogenesis via VEGF and metastasis [161]. Targeting this pathway with CXCR7 inhibitors or modulators can inhibit cancer progression [161]. The higher CXCR7 expression is associated with tumors with high grades in prostate and breast cancers [165, 166]. Such chemokine grade prevents apoptosis and enhances adhesive and invasive activities of tumor cells that leads to metastasis. CXCR7 expression also promotes the release of interleukin 8 (IL-8), and VEGF, and thereby supports prostate tumor cells’ survival [165]. The co-expression of CXCR7 and CXCR4 could activate ERK and AKT signaling to promote of breast cancer cells proliferation and survival. Therefore, targeting the CXCL12/CXCL11/CXCR7 axis by pharmacological inhibitors could be an excellent approach for preventing distant metastasis of breast cancer [165, 166].

3.4.3. CCL2-CCR2 axis

CCL2, a low molecular weight chemotactic cytokine, is involved in tumorigenesis, angiogenesis, and metastasis [167, 168]. CCL2 binds to the receptor CCR2 and initiates several pro-inflammatory effects and the neo-angiogenesis process [169]. CCL2 and CCR2 is associated with cancer progression in various cancers, including breast and lung cancers [169]. A high level of CCL2 ligand is present in the serum of obese and metastatic cancer patients [168, 169]. This increase suggests that CCL2/CCR2 axis could be a potential therapeutic approach for metastatic patients. During inflammation, the recruitment of monocytes in the tumor induces the CCL2/CCR2 activation, which is essential for forming the metastatic microenvironment [168]. The CCL2/CCR2 pathway is a key signal for early and late stages of cancer metastasis [167]. Activation of the CCL2/CCR2 axis initiates tumor promotion and hijacks the support of the host environment for tumor progression [167]. During metastasis, phenotypic changes occur in cancer cells, break down of the ECM, invade the adjacent tissue, and finally move to distant destinations of the body through the systemic circulation. CCL2 is the primary regulator of this process by guiding the cell migration through CCR2 expressed on the tumor cell surface [167]. In circulation, an increase in CCL2 expression enhances tumor cell proliferation, reduces apoptosis, and increases metastatic potential [95]. Inhibition of the CCL2/CCR2 axis attenuates inflammatory immune cell infiltrations and thereby cancer metastasis in a preclinical mouse model [169]. CCL2 promotes monocyte migration into the breast cancer TME of primary and metastatic locations. This monocyte accumulation increases angiogenesis and cancer cell motility. In breast cancer BrM, CCL2 expression is increased by NF-kB activation. This leads to the recruitment of immune cells expressing CCR2, promoting brain metastasis outgrowth after cancer cell extravasation [95, 170]. CCL2 produced via activated astrocytes enhance brain metastasis via promoting transmigration in CCR2 dependent manner [171]. The proliferation of metastatic cells is seen at the metastatic site by increasing IL-6 and STAT3 phosphorylation levels. Hence, an increase in CCL2 decreases the rate of survival in breast cancer patients. Neutralization, deletion, or genetic modification of CCL2 or CCR2 reduces metastatic potential and increases survival [172]. Thus, CCL2 could be an essential target for future therapeutic management strategies of cancer metastasis, especially in brain metastasis.

3.4.4. CCL19/CCL21-CCR7 axis

The CCL19/CCL21 ligands bind to CCR7 to promote tissue homeostasis, immune surveillance, and tumorigenesis [173, 174]. This axis induces the pathobiology of breast cancer by initiating cellular proliferation and migration [174]. It enhances calcium mobilization and cell migration through activation of G-protein and downstream ERK 1/2 signaling [175]. The expression of these ligands and their receptor is high in lymph nodes [176]. This is why this receptor is defined as a marker for metastases to lymph nodes in different cancers, such as gastric, breast, and lung cancers [177–179]. In general, CCR7 is up-regulated along with CXCR4. In the case of BC metastasis, these two receptors, CCR7 and CXCR4, interact with each other and form heterodimers to activate alternative signaling pathways and promote metastatic phenotype [177, 180]. Some studies reported that T-cell acute lymphoblastic leukemia (T-ALL) metastasize to CNS in a CCR7 dependent manner via activation of notch signaling. The notch gene mutations reinforce T-ALL cells in CNS [181, 182]. Interaction of CCR7 with its ligand CCL19 induces CNS infiltration resulting in decreased survival. Thus, CCR7/CCL19 axis is associated with an increase in the brain and spinal cord infiltration rate, and their knockdown inhibits the CNS metastasis [181, 183]. The binding of CCL19/CCL21 with CCR7 has been shown to enhance directional metastasis of melanoma and breast cancer [176, 183, 184]. In the case of BC, hypoxia induces CCR7 expression through endothelin receptor activation via hypoxia-inducible factor 1 (HIF-1) [185]. The epigenetic machinery of DNA methylation and histone acetylation also enhances the upregulation of CCR7 [186]. The interaction of CCR7 with CCL21 induces actin polymerization for increased cell motility [187, 188]. This interaction activates AKT with the induction of many intracellular targets to promote breast cancer progression and metastasis [189–192].

3.4.5. CCL17/CCL22-CCR4 axis

The CCL17/CCL22/CCR4 axis regulates the cellular trafficking of various types of leukocytes, especially those mediated by Tregs and Th2 cells [193]. These chemokines are essential for immune system development, homeostasis, and functioning. In squamous cell carcinoma, these chemokines significantly impact the brain-derived endothelial cells involved in angiogenesis or angiostasis [194, 195] and metastasis [193]. In ovarian cancer, CCR4 expressing Tregs migrate towards the TME in response to CCL22 and promote tumor growth [195]. An increase in the CCR4/CCL22 axis is associated with BrM of melanoma and shows the differential expression or activation of AKT [10, 195]. In melanoma, it has been reported that soluble factors released by the brain microenvironment enhance CCR4 expression using a preclinical mouse model of brain metastasis [196]. Although CCL17/CCL22 expression is reported in liver and lungs, CCR4 expressing brain intrinsic melanoma cells are infiltrated only in the brain of the mouse [195]. Interestingly, it has been reported that CCR4 ligands enhance in melanoma cells cocultured with microglia in conditioned medium (CM) of BrM melanoma cells [197]. In addition, overexpression of CCR4 enhances tumor cell motility and survival towards the brain via recombinant CCL17 or CM derived from astrocytes [197]. These studies suggest that brain residing CCL17/CCL22 ligands direct CCR4+ melanoma cells towards the brain. This tumor growth and migration have been significantly reduced by anti-CCL17 antibody or CCR4 antagonist [198]. In the brain, the disseminated melanoma cells induce astrocyte cells to produce the pro-inflammatory cytokine IL-23 and increase the expression of MMP2 to enhance the migration and invasion of melanoma cells [198]. In addition, an increase in the expression of CCR4 promotes metastasis of colorectal cancer by enhancing matrix-metalloproteinase 13 (MMP13) expression in NFκB/ERK-dependent manner through CCR4/CCL17-induced Rhokinase cascade [199]. Altogether, the activation of CCR4/CCL17/CCL22 axis upregulates the MMPs expression and thereby enhances the cell migration, invasion, and BrM.

4. Therapeutic Implications of Chemokines in Brain metastasis

Tumor heterogeneity is a major hurdle for developing efficacious therapeutics against metastatic cancer cells. Thus new therapies are needed to overcome heterogeneity in primary as well as metastatic tumors [15]. This tumor heterogeneity responds variably to different treatments like chemotherapy, immunotherapy, and radiotherapy [15]. Chemokines axes have various functions in cancers, and targeting these axes is currently being evaluated in clinical and preclinical settings [200]. Change in chemokine expression promotes growth and survival and directs the metastatic cell towards the target organ [201]. These altered chemokines influence the activation and proliferation of cancer cells in pathological conditions. Targeting these altered chemokines and their receptors could be an attractive therapeutic approach for the management of cancer metastasis and currently, lot of chemokine-targeting based studies are underway for the evaluation. Synthetic and natural small molecules and modulators of chemokines may prove to be an alternative approach with a potential in cancer therapeutics (Table 2).

Table 2.

Inhibitors of chemokines and their receptors evaluated in preclinical and clinical studies.

Preclinical Model

Cancer Type	Chemokine/receptor	Therapy/inhibitor
Breast Cancer	CCL2, CCR2 CXCR4	CNTO888+Radiotherapy, CCX9588+anti-PD-L1 Ly2510924, Balixafortide+Eribulin USL311+lomustine, Reparixin + PTX, GST-NT2 1MP, AMD3465, T22, TN14003, CTCE-9908, ALX40–4C AMD11070 AMD3465 AMD 3100 (Plerixafor) AMD070 (Mavorixafor), AMD11070, nonmacrocyclic TG-0054 (Burixafor), and cyclo-peptide POL6326 (Balixafortide)

Lung cancer	CCR4 CXCR4	AF39/420/1802 AMD3100+VIC-008, LY2510924

Brain Cancer	CXCR4	PRX177561+ Bevacizumab, POL5551+ aVEGF, USL311+ Lomustine, AMD3100

Skin cancer	CCR4	AF399/420/1802

Colon and gastric cancer	CCR4 CCR7 CXCR4	AF399/420/1802 siRNA LY2510924

Pancreatic Cancer	CCR2 CXCR4	PF-0413630+nab-PTX+GEM PF-04136309+GEM, PF0413630 +FX, CCX872 +anti-PD-1, CCX872 +FX, AMD3100 + anti PD-L1

Clinical Model

Chemokine/receptor	Therapy/inhibitor	Clinical Trials

CCR2	PF-04136309+nab- PTX+GEM PF-04136309 + FX CCX872 +FX	Pancreatic cancer NCT02732938 Pancreatic ductal adenocarcinoma NCT01413022 Pancreatic cancer NCT02345408
CCL2	CNTO 888	Solid tumors NCT00537368 Metastatic prostate cancer, NCT00992186
CXCR2	AZD5069 Reparixin + PTX	Pancreatic cancer (NCT02583477) Breast cancer (NCT02370238 (70)
CXCR4	AMD3100 LY2510924	Relapsed AML NCT00512252 lung, breast cancer NCT02737072 Solid tumors NCT02765165
	SX-682 USL311 + Lomustine Balixafortide + Eribulin	Melanoma NCT03161431 HER2−metastatic breast cancer NCT01837095

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4.1. CXCL12-CXCR4/CXCR7 axis

Targeting CXCL12/CXCR4/CXCR7 pathway is one of the potential therapeutic strategies to attenuate CXCL12-induced oncogenic signaling [202]. Multiple antagonists have been used for CXCR4 receptors, such as ALX40–4C, AMD3100, CTCE-9908, T22, and TN14003. These antagonists are designed based on synthetic peptides against the CXCL12 amino-terminal [202]. TN14003, an amidating form of the carboxy terminus of T140, has been used to investigate the effect of 14-mer peptide synthetic antagonist (TN14003) for attenuating metastasis in an animal model [203]. T140 inhibits BC metastasis and is an important tool for the diagnosis of CXCR4 present in cancer cells and tissues [203]. CTCE-9908 has been reported to inhibit tumor growth and metastasis in animal model of various cancer, including prostate, melanoma, and breast cancers [203–206].

The most widely used antagonist molecules for CXCR4 are AMD3100, AMD11070, and IT1t. AMD3100, an original bicyclam ring tethered by an aromatic bridge, is known as an HIV entry blocker inhibitor. It is the first FDA-approved chemokine receptor antagonist for hematopoietic stem cells [207]. Additional molecules targeting CXCR4 have been developed, and these inhibitors, such as cyclo-peptide POL6326 (Balixafortide), Nonmacrocyclic TG-0054 (Burixafor), AMD070 (Mavorixafor), and AMD11070 have been mofified to increase their bioavailability in vivo. These drugs, including AMD3100, are currently in the clinical trials as sensitizers for treating BC, HIV, and warts hypogammaglobulinemia infections myelokathexis (WHIM) syndrome [208–211]. AMD3100 has already been approved by US FDA for hematopoietic stem cells (HSCs) mobilizer for Multiple myeloma (MM) or Non-Hodgkin’s lymphoma (NHL) disease [212]. The AMD3100 and other CXCR4 inhibitors have been shown to be efficacious in many clinical trials and preclinical trials. The efficacy of AMD3100 and its derivative AMD3465 has been tested to mobilize cancer cells from protected sanctuary [200]. These small molecules have very prominent antitumor and antimetastatic effects. CXCR4 expression is increased during glioblastoma (GBM) progression, and its expression is further enhanced by therapies targeting angiogenesis [213]. AMD3465, another CXCR4 inhibitor, has been shown to be effective in medulloblastoma cells and glioblastoma multiforme xenografts [214]. PRX177561 antagonist with bevacizumab and sunitinib enhance antitumor effects via blocking CXCR4 in orthotopic or subcutaneous glioblastoma xenografts models. An NCT02765165 phase I/II clinical trial of CXCR4 inhibitor (USL311) either alone or in combination with Lomustine is currently being tested in recurrent glioblastoma multiform patients [200]. In many preclinical models, AMD3465 and LY2510924 have effectively inhibited tumor growth and metastasis [200, 215, 216]. Phase I trial of LY2510924, Balixafortide and Eribulin has been found to be safe, well-tolerated, and effective against advanced solid cancers as well as in HER2-negative metastatic BC [200, 209, 217]. Nanobodies and antibodies targeting CXCR4 are used against different epitopes on CXCR4 and thus seem attractive for therapies [218]. These therapies if targeting high CXCR4 expressing cells using bivalent moieties with nanobodies coupled to an Fc molecule enhance affinity, bioavailability, and the effector function [219].

A series of the CCX related molecules is synthesized for targeting CXCR7 expression on the cell surface, and these molecules show effective tumor growth inhibition in various preclinical models [207, 220–224]. These small molecule inhibitors (CCX771, CCX266, and CCX733), CXCR7 siRNA, and blocking neutralizing antibodies have shown efficacy in the experimental models [166, 225]. Besides, there is a patent (WO2018019929) available for the ACKR3 antagonists; however, no information is provided for the use of these molecules in cancer models [207]. Furthermore, the 11G8 antibody which is available commercially has been used for the assessment of CXCR7 mediated functional assays [207, 226]. In addition, the heavy chains (nanobodies) have been used for therapeutic purposes [227]. Coupling of the CXCR7 monoclonal antibody with the Fc fragment inhibits CXCL12-mediated signaling with temozolomide, which reduces glioblastoma growth and enhances overall survival in preclinical model [204].

4.2. CCL9/CCL21-CCR7 axis

The use of the CCR7 inhibitor is another valuable, promising therapeutic target. Overexpression of CCR7 in many tumors has been reported to control tumorigenesis. Inhibiting CCR7 via siRNA technology decreases metastasis in multiple animal models [205, 206, 228]. One in vivo study shows that removing the cytoplasmic tail reduces receptor internalization, preventing the adhesion and extravasation [229, 230]. Promising studies have been done using a recombinant CCL21 intra-tumoral injection model that decreases tumor progression and starts the stimulation of cytotoxic immune responses [188, 231]. Another in vitro study shows that CCR7 receptor targeting decreases metastasis incidences [174]. The use of the dendritic cells vaccine significantly reduces the CCL21 level as well as the expression of CCR7, and thus eradicates tumor and metastasis incidences [232]. Therefore, targeting CCR7 strategies may have the potential to chemotherapy drugs for developing combination approaches to eradicate tumor cells and dormant stem like cells.

4.3. CCL2-CCR2 axis

The CCR2/CCL2-axis recruit’s monocytes and promotes pro-tumorigenic and pro-metastatic activities [200]. In a preclinical trial, oral administration of PF-04136309, a CCR2 inhibitor, reduced the number and recruitment of TAMs and significantly affected tumor growth. It can also work synergistically with Gemcitabine (GEM), FOLFIRINOX (FX), and nabPaclitaxel (PTX) [233, 234]. Furthermore, targeting CCR2 therapy along with chemotherapy (FOLFIRINOX) have been well-tolerated and effective [235]. Additional CCR2 targeting studies with 747 antagonists or RDC018 in combination with sorafenib reduced macrophage infiltration and thereby inhibited tumor growth and metastasis [236, 237]. Recent preclinical data showed that inhibition of CCL2 improves radiotherapy and is more effective in BC metastasis [238, 239], and thus targeting the CCL2-CCR2 axis with combinational therapies can be beneficial [238]. The CCR2 antagonist CCX872 is an excellent drug that seems efficacious with checkpoint blockade anti-PD-1 and FX therapies in a clinical trial (NCT02345408) [174, 200]. Moreover, recently in one preclinical study, the inhibition of CCL2 increased radiotherapy efficacy and effectively inhibited metastasis in a breast cancer model [238, 239]. The use of CCR2 inhibitor can also increase the response to peptide vaccination [200]. Overall, blocking the CCL2-CCR2 axis could be a highly advantageous approach for cancer therapy.

4.4. CCL17/CCL22-CCR4 axis

CCR4 expression is generally increased in Cutaneous T cell lymphoma (CTL) and Adult T-cell leukemia (ATL) disease. A phase III clinical trial using Mogamulizumab monoclonal antibody therapy for blocking CCR4 for treating CTL patients has been highly efficacious, leading to better quality of life [240]. In Japan, anti-CCR4 therapy has been used to treat ATL [241]. In one preclinical study, the generation of CAR-T cells against CCR4 helped treat a wide range of T cell malignancies [242]. In preclinical research, Affi5 CCR4 blocking mAb was used in renal cancer. It reduced tumor growth, disrupting myeloid cell phenotype, and increased NK cell infiltration [243]. However, the one significant risk with this antibody is that it induces graftvs-host disease [244]. Therefore small-molecule inhibitor or antagonists of CCR4 with fewer side effect has been developed. One of the small molecule inhibitors of CCR4 is AF399/420/1802, which prevents Treg induction to further improve cancer vaccine’ efficacy in various preclinical mouse models [245].

5. Conclusions and future perspectives

Tumor heterogeneity or subtype switching in BrM strongly suggests that relying only on the primary tumor subtype is not enough for making treatment decisions for metastatic tumors, as these tumors may not have similar molecular features as that of their primary tumors. Another challenge of tumor heterogeneity is the development of therapy resistance. The unavailability of a reliable biomarker for BrM further limits the diagnosis and so as therapy development. Hence, to circumvent these problems, preventive and therapeutic approaches can be developed via targeting chemokine receptors in combination with immunotherapies or chemotherapies.

Chemokine signaling axes are the critical regulators for cancer growth and BrM, and their differential expression at the primary and the metastatic site can be correlated with poor prognosis. In the past decade, multiple studies have been done that enhance our understanding of BrM from various primary sites where It has become clear that chemokines and their receptors could be a promising target for BrM. Several drugs have been used or are now under clinical trials as mentioned, in table 2. Chemokine targeted therapies seem challenging to fit with the current standard of treatments of BrM, however, it could be achieved using high throughput genome sequencing technologies such as scRNA-Seq and immune profiling that can help recognize the targets modulating therapy or immune response.

Researchers worldwide have made tremendous strides in gaining knowledge of chemokine functioning with their specific role in carcinogenesis and metastasis; however, multiple questions still remain unanswered. First, the available chemokine inhibitors, drugs, antibodies, and siRNA shows adverse effects that limit their therapeutic implications. Therefore, the identification of active molecules or regulators that limits the efficacy and are responsible for the toxicity will be helpful to improve the applicability of chemokine targeting drugs/antibodies. Tumor resistance is also a significant factor that limits the response of the drug. Third, developing combinatorial approaches for remarkable and synergistic clinical benefits will be crucial for cancer therapy.

Nevertheless, chemokine targeting has offered a reasonable outlook for cancer associated BrM. Several studies on chemokine cascade have shown better therapeutic benefits. However, not all patients may respond to chemokine inhibitors due to the differential expression or secretion of chemokines and the different receptors for single chemokines with formidable tumor resistance. To expand the use of chemokine therapy, we need to identify regulators of tumor heterogeneity modulating chemokine profiling that can be employed in combinatorial strategies with conventional treatments that can improve the overall outcomes in BrM patients.

Acknowledgments

We thank all our colleagues for giving us their valuable suggestions, precious time for reading, and significant comments for this review. We thank Sameer Mohiuddin for editorial assistance. The BioRender.com is used for creating figures. The study on brain metastasis in our lab is supported by the National Institutes of Health (NIH) grants R01CA241752 and R01CA218545 to MWN. The work of SKB is supported by NIH R01CA247471, R01CA195586, and P01 CA217798. All the presented conclusions derived from interpretations, and opinions in this manuscript are of authors and do not represent the official views of the National Institutes of Health and other funding agencies.

Abbreviations

BrM: Brain metastasis
OS: Overall survival
TME: Tumor microenvironment
BC: Breast cancer
CTC: Circulating tumor cells
CNS: Central nervous system
BBB: Blood-brain-barrier
GPCR: G-protein-coupled transmembrane receptors
ECM: Extracellular matrix
CSCs: Cancer stem cells
CSCs: Cancer stem cells
EMT: Epithelial-mesenchymal transition
MSCs: Mesenchymal stem cells
bFGF: Basic fibroblast growth factor
TGF-β: Transforming growth factor–β
IL-1β: Interleukin-1β
IFN-γ: Interferon-γ
COX2: Cyclooxygenase-2
MMPs: Cyclooxygenase-2 (COX2) Matrix metalloproteinases
PCDH7: Protocadherin 7
CX43: Connexin 43
BMDMs: Bone marrow-derived macrophages
PMN: Pre-metastatic niche
DCC: Disseminated cancer cell
CNS-myeloid: CNS myeloid cells
scRNA-Seq: Single-cell RNA-Sequencing
mTOR: mammalian target of rapamycin
Th1: T helper type 1
CAFs: Cancer-Associated Fibroblasts
HCC: hepatocellular carcinoma
MDSC: myeloid-derived suppressor cells
EGF: epidermal growth factor
TNF-α: tumor necrosis factor-α
FGFs: fibroblast growth factors
ILs: interleukins
TAM: tumor-associated macrophages
GM-CSF: Granulocyte-macrophage colony-stimulating factor
Treg: regulatory T cells
VEGF: vascular endothelial growth factor
T‐ ALL: T‐ cell acute lymphoblastic leukemia
HIF-1: hypoxia-inducible factor 1
ER: Estrogen Receptor
MMP: Matrix-Metalloproteinase

Footnotes

Conflict interest statement

SKB is co-founder of Sanguine Diagnostics and Therapeutics, Inc. Other authors declare no competing interests.

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REFERENCE

[1].Shirahata M, Mishima K, [Metastatic Brain Tumors], Brain Nerve 73(1) (2021) 5–11. 10.11477/mf.1416201707 [DOI] [PubMed] [Google Scholar]
[2].Amin S, Baine MJ, Meza JL, Lin C, Association of Immunotherapy With Survival Among Patients With Brain Metastases Whose Cancer Was Managed With Definitive Surgery of the Primary Tumor, JAMA Netw Open 3(9) (2020) e2015444. 10.1001/jamanetworkopen.2020.15444 [DOI] [PMC free article] [PubMed] [Google Scholar]
[3].Brain metastases, Nat Rev Dis Primers 5(1) (2019) 6. 10.1038/s41572-019-0061-8 [DOI] [PubMed] [Google Scholar]
[4].Valiente M, Ahluwalia MS, Boire A, Brastianos PK, Goldberg SB, Lee EQ, Le Rhun E, Preusser M, Winkler F, Soffietti R, The Evolving Landscape of Brain Metastasis, Trends Cancer 4(3) (2018) 176–196. 10.1016/j.trecan.2018.01.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
[5].Nayak L, Lee EQ, Wen PY, Epidemiology of brain metastases, Curr Oncol Rep 14(1) (2012) 48–54. 10.1007/s11912-011-0203-y [DOI] [PubMed] [Google Scholar]
[6].Ostrom QT, Wright CH, Barnholtz-Sloan JS, Brain metastases: epidemiology, Handb Clin Neurol 149 (2018) 27–42. 10.1016/B978-0-12-811161-1.00002-5 [DOI] [PubMed] [Google Scholar]
[7].Doron H, Pukrop T, Erez N, A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis, Cancer Res 79(3) (2019) 423–436. 10.1158/0008-5472.CAN-18-1805 [DOI] [PMC free article] [PubMed] [Google Scholar]
[8].Chambers AF, Groom AC, MacDonald IC, Dissemination and growth of cancer cells in metastatic sites, Nat Rev Cancer 2(8) (2002) 563–72. 10.1038/nrc865 [DOI] [PubMed] [Google Scholar]
[9].Steeg PS, Tumor metastasis: mechanistic insights and clinical challenges, Nat Med 12(8) (2006) 895–904. 10.1038/nm1469 [DOI] [PubMed] [Google Scholar]
[10].Izraely S, Klein A, Sagi-Assif O, Meshel T, Tsarfaty G, Hoon DS, Witz IP, Chemokine-chemokine receptor axes in melanoma brain metastasis, Immunol Lett 130(1–2) (2010) 107–14. 10.1016/j.imlet.2009.12.003 [DOI] [PubMed] [Google Scholar]
[11].Pedrosa R, Mustafa DA, Soffietti R, Kros JM, Breast cancer brain metastasis: molecular mechanisms and directions for treatment, Neuro Oncol 20(11) (2018) 1439–1449. 10.1093/neuonc/noy044 [DOI] [PMC free article] [PubMed] [Google Scholar]
[12].Chow MT, Luster AD, Chemokines in cancer, Cancer Immunol Res 2(12) (2014) 1125–31. 10.1158/2326-6066.CIR-14-0160 [DOI] [PMC free article] [PubMed] [Google Scholar]
[13].Xun Y, Yang H, Li J, Wu F, Liu F, CXC Chemokine Receptors in the Tumor Microenvironment and an Update of Antagonist Development, Rev Physiol Biochem Pharmacol 178 (2020) 1–40. 10.1007/112_2020_35 [DOI] [PubMed] [Google Scholar]
[14].Sarvaiya PJ, Guo D, Ulasov I, Gabikian P, Lesniak MS, Chemokines in tumor progression and metastasis, Oncotarget 4(12) (2013) 2171–85. 10.18632/oncotarget.1426 [DOI] [PMC free article] [PubMed] [Google Scholar]
[15].Saxena S, Singh RK, Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity, Cancer Metastasis Rev (2021). 10.1007/s10555-021-09970-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
[16].Fidler IJ, The Biology of Brain Metastasis: Challenges for Therapy, Cancer J 21(4) (2015) 284–93. 10.1097/PPO.0000000000000126 [DOI] [PubMed] [Google Scholar]
[17].Hulsbergen AFC, Claes A, Kavouridis VK, Ansaripour A, Nogarede C, Hughes ME, Smith TR, Brastianos PK, Verhoeff JJC, Lin NU, Broekman MLD, Subtype switching in breast cancer brain metastases: a multicenter analysis, Neuro Oncol 22(8) (2020) 1173–1181. 10.1093/neuonc/noaa013 [DOI] [PMC free article] [PubMed] [Google Scholar]
[18].Shih DJHN, Bihun I, Dagogo-Jack I, Gill CM, Aquilanti E, Bertalan M, Kaplan A, D’Andrea MR, Chukwueke U, Ippen FM, Alvarez-Breckenridge C, Camarda ND, Lastrapes M, McCabe D, Kuter B, Kaufman B, Strickland MR, Martinez-Gutierrez JC, Nagabhushan D, De Sauvage M, White MD, Castro BA, Hoang K, Kaneb A, Batchelor ED, Paek SH, Park SH, Martinez-Lage M, Berghoff AS, Merrill P, Gerstner ER, Batchelor TT, Frosch MP, Frazier RP, Borger DR, Iafrate AJ, Johnson BE, Santagata S, Preusser M, Cahill DP, Carter SL, Brastianos PK, Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma, Nat Genet 52(4) (2020) 371–377. 10.1038/s41588-020-0592-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
[19].Han CH, Brastianos PK, Genetic Characterization of Brain Metastases in the Era of Targeted Therapy, Front Oncol 7 (2017) 230. 10.3389/fonc.2017.00230 [DOI] [PMC free article] [PubMed] [Google Scholar]
[20].Kalra J, Baker J, Song J, Kyle A, Minchinton A, Bally M, Inter-Metastatic Heterogeneity of Tumor Marker Expression and Microenvironment Architecture in a Preclinical Cancer Model, Int J Mol Sci 22(12) (2021). 10.3390/ijms22126336 [DOI] [PMC free article] [PubMed] [Google Scholar]
[21].Naito Y, Yamamoto Y, Sakamoto N, Shimomura I, Kogure A, Kumazaki M, Yokoi A, Yashiro M, Kiyono T, Yanagihara K, Takahashi RU, Hirakawa K, Yasui W, Ochiya T, Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts, Oncogene 38(28) (2019) 5566–5579. 10.1038/s41388-019-0832-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
[22].Adekoya TO, Richardson RM, Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis, Int J Mol Sci 21(12) (2020). 10.3390/ijms21124449 [DOI] [PMC free article] [PubMed] [Google Scholar]
[23].Cheng ZH, Shi YX, Yuan M, Xiong D, Zheng JH, Zhang ZY, Chemokines and their receptors in lung cancer progression and metastasis, J Zhejiang Univ Sci B 17(5) (2016) 342–51. 10.1631/jzus.B1500258 [DOI] [PMC free article] [PubMed] [Google Scholar]
[24].Haider MT, Smit DJ, Taipaleenmaki H, The Endosteal Niche in Breast Cancer Bone Metastasis, Front Oncol 10 (2020) 335. 10.3389/fonc.2020.00335 [DOI] [PMC free article] [PubMed] [Google Scholar]
[25].Azizidoost S, Asnafi AA, Saki N, Signaling-chemokine axis network in brain as a sanctuary site for metastasis, J Cell Physiol 234(4) (2019) 3376–3382. 10.1002/jcp.27305 [DOI] [PubMed] [Google Scholar]
[26].Salmaggi A, Maderna E, Calatozzolo C, Gaviani P, Canazza A, Milanesi I, Silvani A, DiMeco F, Carbone A, Pollo B, CXCL12, CXCR4 and CXCR7 expression in brain metastases, Cancer Biol Ther 8(17) (2009) 1608–14. 10.4161/cbt.8.17.9202 [DOI] [PubMed] [Google Scholar]
[27].Guldner IH, Wang Q, Yang L, Golomb SM, Zhao Z, Lopez JA, Brunory A, Howe EN, Zhang Y, Palakurthi B, Barron M, Gao H, Xuei X, Liu Y, Li J, Chen DZ, Landreth GE, Zhang S, CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10, Cell 183(5) (2020) 1234–1248 e25. 10.1016/j.cell.2020.09.064 [DOI] [PMC free article] [PubMed] [Google Scholar]
[28].Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C, Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer, Cell Stem Cell 1(3) (2007) 313–23. 10.1016/j.stem.2007.06.002 [DOI] [PubMed] [Google Scholar]
[29].Norton KA, Popel AS, Pandey NB, Heterogeneity of chemokine cell-surface receptor expression in triple-negative breast cancer, Am J Cancer Res 5(4) (2015) 1295–307. [PMC free article] [PubMed] [Google Scholar]
[30].Fares J, Cordero A, Kanojia D, Lesniak MS, The Network of Cytokines in Brain Metastases, Cancers (Basel) 13(1) (2021). 10.3390/cancers13010142 [DOI] [PMC free article] [PubMed] [Google Scholar]
[31].Kim BJ, Hannanta-Anan P, Ryd A, Swartz MA, Wu M, Lymphoidal chemokine CCL19 promoted the heterogeneity of the breast tumor cell motility within a 3D microenvironment revealed by a Levy distribution analysis, Integr Biol (Camb) 12(1) (2020) 12–20. 10.1093/intbio/zyaa001 [DOI] [PMC free article] [PubMed] [Google Scholar]
[32].Morein D, Erlichman N, Ben-Baruch A, Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy, Front Immunol 11 (2020) 952. 10.3389/fimmu.2020.00952 [DOI] [PMC free article] [PubMed] [Google Scholar]
[33].Ben-Baruch A, Organ selectivity in metastasis: regulation by chemokines and their receptors, Clin Exp Metastasis 25(4) (2008) 345–56. 10.1007/s10585-007-9097-3 [DOI] [PubMed] [Google Scholar]
[34].Kim J, Mori T, Chen SL, Amersi FF, Martinez SR, Kuo C, Turner RR, Ye X, Bilchik AJ, Morton DL, Hoon DS, Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome, Ann Surg 244(1) (2006) 113–20. 10.1097/01.sla.0000217690.65909.9c [DOI] [PMC free article] [PubMed] [Google Scholar]
[35].Murakami T, Cardones AR, Hwang ST, Chemokine receptors and melanoma metastasis, J Dermatol Sci 36(2) (2004) 71–8. 10.1016/j.jdermsci.2004.03.002 [DOI] [PubMed] [Google Scholar]
[36].Nagarsheth N, Wicha MS, Zou W, Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy, Nat Rev Immunol 17(9) (2017) 559–572. 10.1038/nri.2017.49 [DOI] [PMC free article] [PubMed] [Google Scholar]
[37].Siegel RL, Miller KD, Jemal A, Cancer statistics, 2016, CA Cancer J Clin 66(1) (2016) 7–30. 10.3322/caac.21332 [DOI] [PubMed] [Google Scholar]
[38].Runa F, Hamalian S, Meade K, Shisgal P, Gray PC, Kelber JA, Tumor microenvironment heterogeneity: challenges and opportunities, Curr Mol Biol Rep 3(4) (2017) 218–229. 10.1007/s40610-017-0073-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
[39].Barron DA, Rowley DR, The reactive stroma microenvironment and prostate cancer progression, Endocr Relat Cancer 19(6) (2012) R187–204. 10.1530/ERC-12-0085 [DOI] [PMC free article] [PubMed] [Google Scholar]
[40].Hanahan D, Coussens LM, Accessories to the crime: functions of cells recruited to the tumor microenvironment, Cancer Cell 21(3) (2012) 309–22. 10.1016/j.ccr.2012.02.022 [DOI] [PubMed] [Google Scholar]
[41].Kalluri R, The biology and function of fibroblasts in cancer, Nat Rev Cancer 16(9) (2016) 582–98. 10.1038/nrc.2016.73 [DOI] [PubMed] [Google Scholar]
[42].McAllister SS, Weinberg RA, The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis, Nat Cell Biol 16(8) (2014) 717–27. 10.1038/ncb3015 [DOI] [PMC free article] [PubMed] [Google Scholar]
[43].Shiao SL, Chu GC, Chung LW, Regulation of prostate cancer progression by the tumor microenvironment, Cancer Lett 380(1) (2016) 340–8. 10.1016/j.canlet.2015.12.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
[44].Kim J, DeBerardinis RJ, Mechanisms and Implications of Metabolic Heterogeneity in Cancer, Cell Metab 30(3) (2019) 434–446. 10.1016/j.cmet.2019.08.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
[45].Quail DF, Joyce JA, Microenvironmental regulation of tumor progression and metastasis, Nat Med 19(11) (2013) 1423–37. 10.1038/nm.3394 [DOI] [PMC free article] [PubMed] [Google Scholar]
[46].Quail DF, Joyce JA, The Microenvironmental Landscape of Brain Tumors, Cancer Cell 31(3) (2017) 326–341. 10.1016/j.ccell.2017.02.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
[47].Balkwill FR, Capasso M, Hagemann T, The tumor microenvironment at a glance, J Cell Sci 125(Pt 23) (2012) 5591–6. 10.1242/jcs.116392 [DOI] [PubMed] [Google Scholar]
[48].Burgos-Panadero R, Lucantoni F, Gamero-Sandemetrio E, Cruz-Merino L, Alvaro T, Noguera R, The tumour microenvironment as an integrated framework to understand cancer biology, Cancer Lett 461 (2019) 112–122. 10.1016/j.canlet.2019.07.010 [DOI] [PubMed] [Google Scholar]
[49].Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K, Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity, Nature 514(7520) (2014) 54–8. 10.1038/nature13556 [DOI] [PMC free article] [PubMed] [Google Scholar]
[50].Engelhardt B, Vajkoczy P, Weller RO, The movers and shapers in immune privilege of the CNS, Nat Immunol 18(2) (2017) 123–131. 10.1038/ni.3666 [DOI] [PubMed] [Google Scholar]
[51].Louveau A, Harris TH, Kipnis J, Revisiting the Mechanisms of CNS Immune Privilege, Trends Immunol 36(10) (2015) 569–577. 10.1016/j.it.2015.08.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
[52].Huang X, Hussain B, Chang J, Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms, CNS Neurosci Ther 27(1) (2021) 36–47. 10.1111/cns.13569 [DOI] [PMC free article] [PubMed] [Google Scholar]
[53].Rhea EM, Banks WA, Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance, Front Neurosci 13 (2019) 521. 10.3389/fnins.2019.00521 [DOI] [PMC free article] [PubMed] [Google Scholar]
[54].Tata M, Ruhrberg C, Fantin A, Vascularisation of the central nervous system, Mech Dev 138 Pt 1 (2015) 26–36. 10.1016/j.mod.2015.07.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
[55].Tian L, Ma L, Kaarela T, Li Z, Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases, J Neuroinflammation 9 (2012) 155. 10.1186/1742-2094-9-155 [DOI] [PMC free article] [PubMed] [Google Scholar]
[56].Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J, Structural and functional features of central nervous system lymphatic vessels, Nature 523(7560) (2015) 337–41. 10.1038/nature14432 [DOI] [PMC free article] [PubMed] [Google Scholar]
[57].Ndubuizu O, LaManna JC, Brain tissue oxygen concentration measurements, Antioxid Redox Signal 9(8) (2007) 1207–19. 10.1089/ars.2007.1634 [DOI] [PubMed] [Google Scholar]
[58].Lowery FJ, Yu D, Brain metastasis: Unique challenges and open opportunities, Biochim Biophys Acta Rev Cancer 1867(1) (2017) 49–57. 10.1016/j.bbcan.2016.12.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
[59].Weber CE, Kuo PC, The tumor microenvironment, Surg Oncol 21(3) (2012) 172–7. 10.1016/j.suronc.2011.09.001 [DOI] [PubMed] [Google Scholar]
[60].Witz IP, Levy-Nissenbaum O, The tumor microenvironment in the post-PAGET era, Cancer Lett 242(1) (2006) 1–10. 10.1016/j.canlet.2005.12.005 [DOI] [PubMed] [Google Scholar]
[61].Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L, Macrophages and Metabolism in the Tumor Microenvironment, Cell Metab 30(1) (2019) 36–50. 10.1016/j.cmet.2019.06.001 [DOI] [PubMed] [Google Scholar]
[62].Hill BS, Sarnella A, D’Avino G, Zannetti A, Recruitment of stromal cells into tumour microenvironment promote the metastatic spread of breast cancer, Semin Cancer Biol 60 (2020) 202–213. 10.1016/j.semcancer.2019.07.028 [DOI] [PubMed] [Google Scholar]
[63].Pickup MW, Mouw JK, Weaver VM, The extracellular matrix modulates the hallmarks of cancer, EMBO Rep 15(12) (2014) 1243–53. 10.15252/embr.201439246 [DOI] [PMC free article] [PubMed] [Google Scholar]
[64].Guo S, Deng CX, Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation, Int J Biol Sci 14(14) (2018) 2083–2093. 10.7150/ijbs.25720 [DOI] [PMC free article] [PubMed] [Google Scholar]
[65].Welch DR, Hurst DR, Defining the Hallmarks of Metastasis, Cancer Res 79(12) (2019) 3011–3027. 10.1158/0008-5472.CAN-19-0458 [DOI] [PMC free article] [PubMed] [Google Scholar]
[66].Shibue T, Weinberg RA, EMT, CSCs, and drug resistance: the mechanistic link and clinical implications, Nat Rev Clin Oncol 14(10) (2017) 611–629. 10.1038/nrclinonc.2017.44 [DOI] [PMC free article] [PubMed] [Google Scholar]
[67].Morad G, Moses MA, Brainwashed by extracellular vesicles: the role of extracellular vesicles in primary and metastatic brain tumour microenvironment, J Extracell Vesicles 8(1) (2019) 1627164. 10.1080/20013078.2019.1627164 [DOI] [PMC free article] [PubMed] [Google Scholar]
[68].Broekman ML, Maas SLN, Abels ER, Mempel TR, Krichevsky AM, Breakefield XO, Multidimensional communication in the microenvirons of glioblastoma, Nat Rev Neurol 14(8) (2018) 482–495. 10.1038/s41582-018-0025-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
[69].Steeg PS, Camphausen KA, Smith QR, Brain metastases as preventive and therapeutic targets, Nat Rev Cancer 11(5) (2011) 352–63. 10.1038/nrc3053 [DOI] [PMC free article] [PubMed] [Google Scholar]
[70].Abbott NJ, Dynamics of CNS barriers: evolution, differentiation, and modulation, Cell Mol Neurobiol 25(1) (2005) 5–23. 10.1007/s10571-004-1374-y [DOI] [PMC free article] [PubMed] [Google Scholar]
[71].Fakhrejahani E, Toi M, Tumor angiogenesis: pericytes and maturation are not to be ignored, J Oncol 2012 (2012) 261750. 10.1155/2012/261750 [DOI] [PMC free article] [PubMed] [Google Scholar]
[72].Strell C, Entschladen F, Extravasation of leukocytes in comparison to tumor cells, Cell Commun Signal 6 (2008) 10. 10.1186/1478-811X-6-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
[73].Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA, Massague J, Genes that mediate breast cancer metastasis to the brain, Nature 459(7249) (2009) 1005–9. 10.1038/nature08021 [DOI] [PMC free article] [PubMed] [Google Scholar]
[74].Boecke A, Carstens AC, Neacsu CD, Baschuk N, Haubert D, Kashkar H, Utermohlen O, Pongratz C, Kronke M, TNF-receptor-1 adaptor protein FAN mediates TNF-induced B16 melanoma motility and invasion, Br J Cancer 109(2) (2013) 422–32. 10.1038/bjc.2013.242 [DOI] [PMC free article] [PubMed] [Google Scholar]
[75].Lucas JT Jr., Salimath BP, Slomiany MG, Rosenzweig SA, Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent, Oncogene 29(31) (2010) 4449–59. 10.1038/onc.2010.185 [DOI] [PMC free article] [PubMed] [Google Scholar]
[76].Stamatovic SM, Keep RF, Andjelkovic AV, Brain endothelial cell-cell junctions: how to “open” the blood brain barrier, Curr Neuropharmacol 6(3) (2008) 179–92. 10.2174/157015908785777210 [DOI] [PMC free article] [PubMed] [Google Scholar]
[77].Sevenich L, Joyce JA, Pericellular proteolysis in cancer, Genes Dev 28(21) (2014) 2331–47. 10.1101/gad.250647.114 [DOI] [PMC free article] [PubMed] [Google Scholar]
[78].Huchzermeyer C, Berndt N, Holzhutter HG, Kann O, Oxygen consumption rates during three different neuronal activity states in the hippocampal CA3 network, J Cereb Blood Flow Metab 33(2) (2013) 263–71. 10.1038/jcbfm.2012.165 [DOI] [PMC free article] [PubMed] [Google Scholar]
[79].Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, Winkler F, Real-time imaging reveals the single steps of brain metastasis formation, Nat Med 16(1) (2010) 116–22. 10.1038/nm.2072 [DOI] [PubMed] [Google Scholar]
[80].Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, Chaft JE, Kris MG, Huse JT, Brogi E, Massague J, Serpins promote cancer cell survival and vascular co-option in brain metastasis, Cell 156(5) (2014) 1002–16. 10.1016/j.cell.2014.01.040 [DOI] [PMC free article] [PubMed] [Google Scholar]
[81].Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ, Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF, Science 284(5422) (1999) 1994–8. 10.1126/science.284.5422.1994 [DOI] [PubMed] [Google Scholar]
[82].Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, Gerald WL, Massague J, WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis, Cell 138(1) (2009) 51–62. 10.1016/j.cell.2009.04.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
[83].Lorger M, Felding-Habermann B, Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis, Am J Pathol 176(6) (2010) 2958–71. 10.2353/ajpath.2010.090838 [DOI] [PMC free article] [PubMed] [Google Scholar]
[84].Berghoff AS, Rajky O, Winkler F, Bartsch R, Furtner J, Hainfellner JA, Goodman SL, Weller M, Schittenhelm J, Preusser M, Invasion patterns in brain metastases of solid cancers, Neuro Oncol 15(12) (2013) 1664–72. 10.1093/neuonc/not112 [DOI] [PMC free article] [PubMed] [Google Scholar]
[85].Bentolila LA, Prakash R, Mihic-Probst D, Wadehra M, Kleinman HK, Carmichael TS, Peault B, Barnhill RL, Lugassy C, Imaging of Angiotropism/Vascular Co-Option in a Murine Model of Brain Melanoma: Implications for Melanoma Progression along Extravascular Pathways, Sci Rep 6 (2016) 23834. 10.1038/srep23834 [DOI] [PMC free article] [PubMed] [Google Scholar]
[86].Carbonell WS, Ansorge O, Sibson N, Muschel R, The vascular basement membrane as “soil” in brain metastasis, PLoS One 4(6) (2009) e5857. 10.1371/journal.pone.0005857 [DOI] [PMC free article] [PubMed] [Google Scholar]
[87].Garcia MA, Lazar A, Duriseti S, Raleigh DR, Hess CP, Fogh SE, Barani IJ, Nakamura JL, Larson DA, Theodosopoulos P, McDermott M, Sneed PK, Braunstein S, Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes, J Neurosurg 126(6) (2017) 1756–1763. 10.3171/2016.4.JNS152319 [DOI] [PubMed] [Google Scholar]
[88].Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, Jacob L, Patwa R, Shah H, Xu K, Cross JR, Massague J, Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer, Nature 533(7604) (2016) 493–498. 10.1038/nature18268 [DOI] [PMC free article] [PubMed] [Google Scholar]
[89].Xing F, Kobayashi A, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Wilber A, Mo YY, Moore BE, Liu W, Fukuda K, Iiizumi M, Sharma S, Liu Y, Wu K, Peralta E, Watabe K, Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain, EMBO Mol Med 5(3) (2013) 384–96. 10.1002/emmm.201201623 [DOI] [PMC free article] [PubMed] [Google Scholar]
[90].Lin Q, Balasubramanian K, Fan D, Kim SJ, Guo L, Wang H, Bar-Eli M, Aldape KD, Fidler IJ, Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels, Neoplasia 12(9) (2010) 748–54. 10.1593/neo.10602 [DOI] [PMC free article] [PubMed] [Google Scholar]
[91].Stoletov K, Strnadel J, Zardouzian E, Momiyama M, Park FD, Kelber JA, Pizzo DP, Hoffman R, VandenBerg SR, Klemke RL, Role of connexins in metastatic breast cancer and melanoma brain colonization, J Cell Sci 126(Pt 4) (2013) 904–13. 10.1242/jcs.112748 [DOI] [PMC free article] [PubMed] [Google Scholar]
[92].Kim SJ, Kim JS, Park ES, Lee JS, Lin Q, Langley RR, Maya M, He J, Kim SW, Weihua Z, Balasubramanian K, Fan D, Mills GB, Hung MC, Fidler IJ, Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy, Neoplasia 13(3) (2011) 286–98. 10.1593/neo.11112 [DOI] [PMC free article] [PubMed] [Google Scholar]
[93].Adkins CE, Mohammad AS, Terrell-Hall TB, Dolan EL, Shah N, Sechrest E, Griffith J, Lockman PR, Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer, Clin Exp Metastasis 33(4) (2016) 373–83. 10.1007/s10585-016-9784-z [DOI] [PMC free article] [PubMed] [Google Scholar]
[94].Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR, Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer, Clin Cancer Res 16(23) (2010) 5664–78. 10.1158/1078-0432.CCR-10-1564 [DOI] [PMC free article] [PubMed] [Google Scholar]
[95].Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C, Wang H, Ellis K, Cheerathodi M, McCarty JH, Palmieri D, Saunus J, Lakhani S, Huang S, Sahin AA, Aldape KD, Steeg PS, Yu D, Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth, Nature 527(7576) (2015) 100–104. 10.1038/nature15376 [DOI] [PMC free article] [PubMed] [Google Scholar]
[96].Dickens AM, Tovar YRLB, Yoo SW, Trout AL, Bae M, Kanmogne M, Megra B, Williams DW, Witwer KW, Gacias M, Tabatadze N, Cole RN, Casaccia P, Berman JW, Anthony DC, Haughey NJ, Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions, Sci Signal 10(473) (2017). 10.1126/scisignal.aai7696 [DOI] [PMC free article] [PubMed] [Google Scholar]
[97].Schwartz H, Blacher E, Amer M, Livneh N, Abramovitz L, Klein A, Ben-Shushan D, Soffer S, Blazquez R, Barrantes-Freer A, Muller M, Muller-Decker K, Stein R, Tsarfaty G, Satchi-Fainaro R, Umansky V, Pukrop T, Erez N, Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation, Cancer Res 76(15) (2016) 4359–71. 10.1158/0008-5472.CAN-16-0485 [DOI] [PubMed] [Google Scholar]
[98].Doron H, Amer M, Ershaid N, Blazquez R, Shani O, Lahav TG, Cohen N, Adler O, Hakim Z, Pozzi S, Scomparin A, Cohen J, Yassin M, Monteran L, Grossman R, Tsarfaty G, Luxenburg C, Satchi-Fainaro R, Pukrop T, Erez N, Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis, Cell Rep 28(7) (2019) 1785–1798 e6. 10.1016/j.celrep.2019.07.033 [DOI] [PubMed] [Google Scholar]
[99].Burn L, Gutowski N, Whatmore J, Giamas G, Pranjol MZI, The role of astrocytes in brain metastasis at the interface of circulating tumour cells and the blood brain barrier, Front Biosci (Landmark Ed) 26(9) (2021) 590–601. 10.52586/4969 [DOI] [PubMed] [Google Scholar]
[100].Sturtzel C, Hocking J, Kirchberger S, Distel M, Studying the Tumor Microenvironment in Zebrafish, Adv Exp Med Biol 1329 (2021) 69–92. 10.1007/978-3-030-73119-9_4 [DOI] [PubMed] [Google Scholar]
[101].Shen Y, Zhang B, Wei X, Guan X, Zhang W, CXCL8 is a prognostic biomarker and correlated with TNBC brain metastasis and immune infiltration, Int Immunopharmacol 103 (2021) 108454. 10.1016/j.intimp.2021.108454 [DOI] [PubMed] [Google Scholar]
[102].Duan S, Wang S, Huang T, Wang J, Yuan X, circRNAs: Insight Into Their Role in Tumor-Associated Macrophages, Front Oncol 11 (2021) 780744. 10.3389/fonc.2021.780744 [DOI] [PMC free article] [PubMed] [Google Scholar]
[103].Cacho-Diaz B, Garcia-Botello DR, Wegman-Ostrosky T, Reyes-Soto G, Ortiz-Sanchez E, Herrera-Montalvo LA, Tumor microenvironment differences between primary tumor and brain metastases, J Transl Med 18(1) (2020) 1. 10.1186/s12967-019-02189-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
[104].Wu SY, Xing F, Sharma S, Wu K, Tyagi A, Liu Y, Zhao D, Deshpande RP, Shiozawa Y, Ahmed T, Zhang W, Chan M, Ruiz J, Lycan TW, Dothard A, Watabe K, Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function, J Exp Med 217(8) (2020). 10.1084/jem.20191131 [DOI] [PMC free article] [PubMed] [Google Scholar]
[105].Blazquez R, Wlochowitz D, Wolff A, Seitz S, Wachter A, Perera-Bel J, Bleckmann A, Beissbarth T, Salinas G, Riemenschneider MJ, Proescholdt M, Evert M, Utpatel K, Siam L, Schatlo B, Balkenhol M, Stadelmann C, Schildhaus HU, Korf U, Reinz E, Wiemann S, Vollmer E, Schulz M, Ritter U, Hanisch UK, Pukrop T, PI3K: A master regulator of brain metastasis-promoting macrophages/microglia, Glia 66(11) (2018) 2438–2455. 10.1002/glia.23485 [DOI] [PubMed] [Google Scholar]
[106].Chuang HN, van Rossum D, Sieger D, Siam L, Klemm F, Bleckmann A, Bayerlova M, Farhat K, Scheffel J, Schulz M, Dehghani F, Stadelmann C, Hanisch UK, Binder C, Pukrop T, Carcinoma cells misuse the host tissue damage response to invade the brain, Glia 61(8) (2013) 1331–46. 10.1002/glia.22518 [DOI] [PMC free article] [PubMed] [Google Scholar]
[107].Jin J, Zhao Q, Emerging role of mTOR in tumor immune contexture: Impact on chemokine-related immune cells migration, Theranostics 10(14) (2020) 6231–6244. 10.7150/thno.45219 [DOI] [PMC free article] [PubMed] [Google Scholar]
[108].Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, Lanitis E, Duraiswamy J, Tanyi JL, Benencia F, Conejo-Garcia J, Ramay HR, Montone KT, Powell DJ Jr., Gimotty PA, Facciabene A, Jackson DG, Weber JS, Rodig SJ, Hodi SF, Kandalaft LE, Irving M, Zhang L, Foukas P, Rusakiewicz S, Delorenzi M, Coukos G, Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors, Cancer Cell 35(6) (2019) 885–900 e10. 10.1016/j.ccell.2019.05.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
[109].Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, Richman LP, Lin JH, Sun YH, Rech AJ, Balli D, Hay CA, Sela Y, Merrell AJ, Liudahl SM, Gordon N, Norgard RJ, Yuan S, Yu S, Chao T, Ye S, Eisinger-Mathason TSK, Faryabi RB, Tobias JW, Lowe SW, Coussens LM, Wherry EJ, Vonderheide RH, Stanger BZ, Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy, Immunity 49(1) (2018) 178–193 e7. 10.1016/j.immuni.2018.06.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
[110].Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Ku AW, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, Evans SS, Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints, Nat Commun 6 (2015) 7458. 10.1038/ncomms8458 [DOI] [PMC free article] [PubMed] [Google Scholar]
[111].Leibold AT, Monaco GN, Dey M, The role of the immune system in brain metastasis, Curr Neurobiol 10(2) (2019) 33–48. [PMC free article] [PubMed] [Google Scholar]
[112].Ishii G, Ochiai A, Neri S, Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment, Adv Drug Deliv Rev 99(Pt B) (2016) 186–196. 10.1016/j.addr.2015.07.007 [DOI] [PubMed] [Google Scholar]
[113].Filer A, Raza K, Salmon M, Buckley CD, The role of chemokines in leucocyte-stromal interactions in rheumatoid arthritis, Front Biosci 13 (2008) 2674–85. 10.2741/2874 [DOI] [PMC free article] [PubMed] [Google Scholar]
[114].Reyes ME, de La Fuente M, Hermoso M, Ili CG, Brebi P, Role of CC Chemokines Subfamily in the Platinum Drugs Resistance Promotion in Cancer, Front Immunol 11 (2020) 901. 10.3389/fimmu.2020.00901 [DOI] [PMC free article] [PubMed] [Google Scholar]
[115].LeBleu VS, Kalluri R, A peek into cancer-associated fibroblasts: origins, functions and translational impact, Dis Model Mech 11(4) (2018). 10.1242/dmm.029447 [DOI] [PMC free article] [PubMed] [Google Scholar]
[116].Qu X, Tang Y, Hua S, Immunological Approaches Towards Cancer and Inflammation: A Cross Talk, Front Immunol 9 (2018) 563. 10.3389/fimmu.2018.00563 [DOI] [PMC free article] [PubMed] [Google Scholar]
[117].Mishra P, Banerjee D, Ben-Baruch A, Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy, J Leukoc Biol 89(1) (2011) 31–9. 10.1189/jlb.0310182 [DOI] [PubMed] [Google Scholar]
[118].Chung B, Esmaeili AA, Gopalakrishna-Pillai S, Murad JP, Andersen ES, Kumar Reddy N, Srinivasan G, Armstrong B, Chu C, Kim Y, Tong T, Waisman J, Yim JH, Badie B, Lee PP, Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12, NPJ Breast Cancer 3 (2017) 6. 10.1038/s41523-017-0008-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
[119].Liu J, Chen S, Wang W, Ning BF, Chen F, Shen W, Ding J, Chen W, Xie WF, Zhang X, Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-beta pathways, Cancer Lett 379(1) (2016) 49–59. 10.1016/j.canlet.2016.05.022 [DOI] [PubMed] [Google Scholar]
[120].Ahirwar DK, Nasser MW, Ouseph MM, Elbaz M, Cuitino MC, Kladney RD, Varikuti S, Kaul K, Satoskar AR, Ramaswamy B, Zhang X, Ostrowski MC, Leone G, Ganju RK, Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation, Oncogene 37(32) (2018) 4428–4442. 10.1038/s41388-018-0263-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
[121].Nwabo Kamdje AH, Kamga PT, Simo RT, Vecchio L, Seke Etet PF, Muller JM, Bassi G, Lukong E, Goel RK, Amvene JM, Krampera M, Mesenchymal stromal cells’ role in tumor microenvironment: involvement of signaling pathways, Cancer Biol Med 14(2) (2017) 129–141. 10.20892/j.issn.2095-3941.2016.0033 [DOI] [PMC free article] [PubMed] [Google Scholar]
[122].Poggi A, Varesano S, Zocchi MR, Corrigendum: How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive, Front Immunol 9 (2018) 1342. 10.3389/fimmu.2018.01342 [DOI] [PMC free article] [PubMed] [Google Scholar]
[123].Bott A, Erdem N, Lerrer S, Hotz-Wagenblatt A, Breunig C, Abnaof K, Worner A, Wilhelm H, Munstermann E, Ben-Baruch A, Wiemann S, miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A, Oncotarget 8(27) (2017) 43897–43914. 10.18632/oncotarget.14915 [DOI] [PMC free article] [PubMed] [Google Scholar]
[124].Donnarumma E, Fiore D, Nappa M, Roscigno G, Adamo A, Iaboni M, Russo V, Affinito A, Puoti I, Quintavalle C, Rienzo A, Piscuoglio S, Thomas R, Condorelli G, Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer, Oncotarget 8(12) (2017) 19592–19608. 10.18632/oncotarget.14752 [DOI] [PMC free article] [PubMed] [Google Scholar]
[125].Gonzalez ME, Martin EE, Anwar T, Arellano-Garcia C, Medhora N, Lama A, Chen YC, Tanager KS, Yoon E, Kidwell KM, Ge C, Franceschi RT, Kleer CG, Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth, Cell Rep 18(5) (2017) 1215–1228. 10.1016/j.celrep.2016.12.079 [DOI] [PMC free article] [PubMed] [Google Scholar]
[126].Luo YP, Zhou H, Krueger J, Kaplan C, Liao D, Markowitz D, Liu C, Chen T, Chuang TH, Xiang R, Reisfeld RA, The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression, Oncogene 29(5) (2010) 662–73. 10.1038/onc.2009.308 [DOI] [PMC free article] [PubMed] [Google Scholar]
[127].McAndrews KM, McGrail DJ, Ravikumar N, Dawson MR, Mesenchymal Stem Cells Induce Directional Migration of Invasive Breast Cancer Cells through TGF-beta, Sci Rep 5 (2015) 16941. 10.1038/srep16941 [DOI] [PMC free article] [PubMed] [Google Scholar]
[128].Wolfe AR, Trenton NJ, Debeb BG, Larson R, Ruffell B, Chu K, Hittelman W, Diehl M, Reuben JM, Ueno NT, Woodward WA, Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models, Oncotarget 7(50) (2016) 82482–82492. 10.18632/oncotarget.12694 [DOI] [PMC free article] [PubMed] [Google Scholar]
[129].Yu PF, Huang Y, Han YY, Lin LY, Sun WH, Rabson AB, Wang Y, Shi YF, TNFalpha-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2(+) neutrophils, Oncogene 36(4) (2017) 482–490. 10.1038/onc.2016.217 [DOI] [PMC free article] [PubMed] [Google Scholar]
[130].An T, Chen Y, Tu Y, Lin P, Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Treatment of Diabetic Foot Ulcers: Application and Challenges, Stem Cell Rev Rep (2020). 10.1007/s12015-020-10014-9 [DOI] [PubMed] [Google Scholar]
[131].Steingen C, Brenig F, Baumgartner L, Schmidt J, Schmidt A, Bloch W, Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells, J Mol Cell Cardiol 44(6) (2008) 1072–84. 10.1016/j.yjmcc.2008.03.010 [DOI] [PubMed] [Google Scholar]
[132].Zhang Y, Hao S, Gao Y, Sun W, Li Y, Decoding Immune Heterogeneity of Melanoma and identifying immune-prognostic hub genes, J Cancer 12(3) (2021) 703–716. 10.7150/jca.50277 [DOI] [PMC free article] [PubMed] [Google Scholar]
[133].Pufnock JS, Rothstein JL, Oncoprotein signaling mediates tumor-specific inflammation and enhances tumor progression, J Immunol 182(9) (2009) 5498–506. 10.4049/jimmunol.0801284 [DOI] [PubMed] [Google Scholar]
[134].Barriga V, Kuol N, Nurgali K, Apostolopoulos V, The Complex Interaction between the Tumor Micro-Environment and Immune Checkpoints in Breast Cancer, Cancers (Basel) 11(8) (2019). 10.3390/cancers11081205 [DOI] [PMC free article] [PubMed] [Google Scholar]
[135].Balkwill F, Charles KA, Mantovani A, Smoldering and polarized inflammation in the initiation and promotion of malignant disease, Cancer Cell 7(3) (2005) 211–7. 10.1016/j.ccr.2005.02.013 [DOI] [PubMed] [Google Scholar]
[136].Gajewski TF, Schreiber H, Fu YX, Innate and adaptive immune cells in the tumor microenvironment, Nat Immunol 14(10) (2013) 1014–22. 10.1038/ni.2703 [DOI] [PMC free article] [PubMed] [Google Scholar]
[137].Comito G, Giannoni E, Segura CP, Barcellos-de-Souza P, Raspollini MR, Baroni G, Lanciotti M, Serni S, Chiarugi P, Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression, Oncogene 33(19) (2014) 2423–31. 10.1038/onc.2013.191 [DOI] [PubMed] [Google Scholar]
[138].Gok Yavuz B, Gunaydin G, Gedik ME, Kosemehmetoglu K, Karakoc D, Ozgur F, Guc D, Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1(+) TAMs, Sci Rep 9(1) (2019) 3172. 10.1038/s41598-01939553-z [DOI] [PMC free article] [PubMed] [Google Scholar]
[139].Yeh CR, Slavin S, Da J, Hsu I, Luo J, Xiao GQ, Ding J, Chou FJ, Yeh S, Estrogen receptor alpha in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment, Mol Cancer 15 (2016) 7. 10.1186/s12943-015-0488-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
[140].Mantovani A, Allavena P, Sica A, Balkwill F, Cancer-related inflammation, Nature 454(7203) (2008) 436–44. 10.1038/nature07205 [DOI] [PubMed] [Google Scholar]
[141].Smith HA, Kang Y, The metastasis-promoting roles of tumor-associated immune cells, J Mol Med (Berl) 91(4) (2013) 411–29. 10.1007/s00109-013-1021-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
[142].Rabinovich GA, Gabrilovich D, Sotomayor EM, Immunosuppressive strategies that are mediated by tumor cells, Annu Rev Immunol 25 (2007) 267–96. 10.1146/annurev.immunol.25.022106.141609 [DOI] [PMC free article] [PubMed] [Google Scholar]
[143].Chittezhath M, Dhillon MK, Lim JY, Laoui D, Shalova IN, Teo YL, Chen J, Kamaraj R, Raman L, Lum J, Thamboo TP, Chiong E, Zolezzi F, Yang H, Van Ginderachter JA, Poidinger M, Wong AS, Biswas SK, Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression, Immunity 41(5) (2014) 815–29. 10.1016/j.immuni.2014.09.014 [DOI] [PubMed] [Google Scholar]
[144].Fleming V, Hu X, Weber R, Nagibin V, Groth C, Altevogt P, Utikal J, Umansky V, Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression, Front Immunol 9 (2018) 398. 10.3389/fimmu.2018.00398 [DOI] [PMC free article] [PubMed] [Google Scholar]
[145].Sokol CL, Luster AD, The chemokine system in innate immunity, Cold Spring Harb Perspect Biol 7(5) (2015). 10.1101/cshperspect.a016303 [DOI] [PMC free article] [PubMed] [Google Scholar]
[146].Ramesh G, MacLean AG, Philipp MT, Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain, Mediators Inflamm 2013 (2013) 480739. 10.1155/2013/480739 [DOI] [PMC free article] [PubMed] [Google Scholar]
[147].Raman D, Baugher PJ, Thu YM, Richmond A, Role of chemokines in tumor growth, Cancer Lett 256(2) (2007) 137–65. 10.1016/j.canlet.2007.05.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
[148].Bian X, Xiao YT, Wu T, Yao M, Du L, Ren S, Wang J, Microvesicles and chemokines in tumor microenvironment: mediators of intercellular communications in tumor progression, Mol Cancer 18(1) (2019) 50. 10.1186/s12943-019-0973-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
[149].Bikfalvi A, Billottet C, The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment, Am J Physiol Cell Physiol 318(3) (2020) C542–C554. 10.1152/ajpcell.00378.2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
[150].Balkwill F, Cancer and the chemokine network, Nat Rev Cancer 4(7) (2004) 540–50. 10.1038/nrc1388 [DOI] [PubMed] [Google Scholar]
[151].Mongan JP, Fadul CE, Cole BF, Zaki BI, Suriawinata AA, Ripple GH, Tosteson TD, Pipas JM, Brain metastases from colorectal cancer: risk factors, incidence, and the possible role of chemokines, Clin Colorectal Cancer 8(2) (2009) 100–5. 10.3816/CCC.2009.n.016 [DOI] [PubMed] [Google Scholar]
[152].Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W, CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks, Oncogene 35(7) (2016) 816–26. 10.1038/onc.2015.139 [DOI] [PubMed] [Google Scholar]
[153].Mortezaee K, CXCL12/CXCR4 axis in the microenvironment of solid tumors: A critical mediator of metastasis, Life Sci 249 (2020) 117534. 10.1016/j.lfs.2020.117534 [DOI] [PubMed] [Google Scholar]
[154].Liu Y, Cao X, Characteristics and Significance of the Pre-metastatic Niche, Cancer Cell 30(5) (2016) 668–681. 10.1016/j.ccell.2016.09.011 [DOI] [PubMed] [Google Scholar]
[155].Wang M, Yang X, Wei M, Wang Z, The Role of CXCL12 Axis in Lung Metastasis of Colorectal Cancer, J Cancer 9(21) (2018) 3898–3903. 10.7150/jca.26383 [DOI] [PMC free article] [PubMed] [Google Scholar]
[156].Cavallaro S, CXCR4/CXCL12 in non-small-cell lung cancer metastasis to the brain, Int J Mol Sci 14(1) (2013) 1713–27. 10.3390/ijms14011713 [DOI] [PMC free article] [PubMed] [Google Scholar]
[157].Huang YC, Hsiao YC, Chen YJ, Wei YY, Lai TH, Tang CH, Stromal cell-derived factor-1 enhances motility and integrin up-regulation through CXCR4, ERK and NF-kappaBdependent pathway in human lung cancer cells, Biochem Pharmacol 74(12) (2007) 1702–12. 10.1016/j.bcp.2007.08.025 [DOI] [PubMed] [Google Scholar]
[158].Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, Pienta KJ, Taichman RS, Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo, J Cell Biochem 89(3) (2003) 462–73. 10.1002/jcb.10522 [DOI] [PubMed] [Google Scholar]
[159].Hinton CV, Avraham S, Avraham HK, Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain, Clin Exp Metastasis 27(2) (2010) 97–105. 10.1007/s10585008-9210-2 [DOI] [PubMed] [Google Scholar]
[160].Scala S, Ottaiano A, Ascierto PA, Cavalli M, Simeone E, Giuliano P, Napolitano M, Franco R, Botti G, Castello G, Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma, Clin Cancer Res 11(5) (2005) 1835–41. 10.1158/1078-0432.CCR-04-1887 [DOI] [PubMed] [Google Scholar]
[161].Huynh C, Dingemanse J, Meyer Zu Schwabedissen HE, Sidharta PN, Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions, Pharmacol Res 161 (2020) 105092. 10.1016/j.phrs.2020.105092 [DOI] [PubMed] [Google Scholar]
[162].Murphy PM, Heusinkveld L, Multisystem multitasking by CXCL12 and its receptors CXCR4 and ACKR3, Cytokine 109 (2018) 2–10. 10.1016/j.cyto.2017.12.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
[163].Lounsbury N, Advances in CXCR7 Modulators, Pharmaceuticals (Basel) 13(2) (2020). 10.3390/ph13020033 [DOI] [PMC free article] [PubMed] [Google Scholar]
[164].Singh AK, Arya RK, Trivedi AK, Sanyal S, Baral R, Dormond O, Briscoe DM, Datta D, Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12, Cytokine Growth Factor Rev 24(1) (2013) 41–9. 10.1016/j.cytogfr.2012.08.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
[165].Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta KJ, Mehra R, Loberg R, Taichman RS, The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer, J Biol Chem 283(7) (2008) 4283–94. 10.1074/jbc.M707465200 [DOI] [PubMed] [Google Scholar]
[166].Wani N, Nasser MW, Ahirwar DK, Zhao H, Miao Z, Shilo K, Ganju RK, C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment, Breast Cancer Res 16(3) (2014) R54. 10.1186/bcr3665 [DOI] [PMC free article] [PubMed] [Google Scholar]
[167].Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ, Targeting the CCL2-CCR2 signaling axis in cancer metastasis, Oncotarget 7(19) (2016) 28697–710. 10.18632/oncotarget.7376 [DOI] [PMC free article] [PubMed] [Google Scholar]
[168].Roblek M, Strutzmann E, Zankl C, Adage T, Heikenwalder M, Atlic A, Weis R, Kungl A, Borsig L, Targeting of CCL2-CCR2-Glycosaminoglycan Axis Using a CCL2 Decoy Protein Attenuates Metastasis through Inhibition of Tumor Cell Seeding, Neoplasia 18(1) (2016) 49–59. 10.1016/j.neo.2015.11.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
[169].Hao Q, Vadgama JV, Wang P, CCL2/CCR2 signaling in cancer pathogenesis, Cell Commun Signal 18(1) (2020) 82. 10.1186/s12964-020-00589-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
[170].Hosonaga M, Saya H, Arima Y, Molecular and cellular mechanisms underlying brain metastasis of breast cancer, Cancer Metastasis Rev 39(3) (2020) 711–720. 10.1007/s10555-02009881-y [DOI] [PMC free article] [PubMed] [Google Scholar]
[171].Hajal C, Shin Y, Li L, Serrano JC, Jacks T, Kamm RD, The CCL2-CCR2 astrocytecancer cell axis in tumor extravasation at the brain, Sci Adv 7(26) (2021). 10.1126/sciadv.abg8139 [DOI] [PMC free article] [PubMed] [Google Scholar]
[172].Hitchcock JR, Watson CJ, Anti-CCL2: building a reservoir or opening the floodgates to metastasis?, Breast Cancer Res 17 (2015) 68. 10.1186/s13058-015-0573-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
[173].Tanaka T, Bai Z, Srinoulprasert Y, Yang BG, Hayasaka H, Miyasaka M, Chemokines in tumor progression and metastasis, Cancer Sci 96(6) (2005) 317–22. 10.1111/j.1349-7006.2005.00059.x [DOI] [PMC free article] [PubMed] [Google Scholar]
[174].Rizeq B, Malki MI, The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression, Cancers (Basel) 12(4) (2020). 10.3390/cancers12041036 [DOI] [PMC free article] [PubMed] [Google Scholar]
[175].Otero C, Groettrup M, Legler DF, Opposite fate of endocytosed CCR7 and its ligands: recycling versus degradation, J Immunol 177(4) (2006) 2314–23. 10.4049/jimmunol.177.4.2314 [DOI] [PubMed] [Google Scholar]
[176].Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A, Involvement of chemokine receptors in breast cancer metastasis, Nature 410(6824) (2001) 50–6. 10.1038/35065016 [DOI] [PubMed] [Google Scholar]
[177].Cabioglu N, Yazici MS, Arun B, Broglio KR, Hortobagyi GN, Price JE, Sahin A, CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer, Clin Cancer Res 11(16) (2005) 5686–93. 10.1158/1078-0432.CCR-05-0014 [DOI] [PubMed] [Google Scholar]
[178].Kato M, Kitayama J, Kazama S, Nagawa H, Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma, Breast Cancer Res 5(5) (2003) R144–50. 10.1186/bcr627 [DOI] [PMC free article] [PubMed] [Google Scholar]
[179].Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, Inoue H, Mori M, Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma, Cancer Res 62(10) (2002) 2937–41. [PubMed] [Google Scholar]
[180].Kochetkova M, Kumar S, McColl SR, Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells, Cell Death Differ 16(5) (2009) 664–73. 10.1038/cdd.2008.190 [DOI] [PubMed] [Google Scholar]
[181].Buonamici S, Trimarchi T, Ruocco MG, Reavie L, Cathelin S, Mar BG, Klinakis A, Lukyanov Y, Tseng JC, Sen F, Gehrie E, Li M, Newcomb E, Zavadil J, Meruelo D, Lipp M, Ibrahim S, Efstratiadis A, Zagzag D, Bromberg JS, Dustin ML, Aifantis I, CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia, Nature 459(7249) (2009) 1000–4. 10.1038/nature08020 [DOI] [PMC free article] [PubMed] [Google Scholar]
[182].Weng AP, Ferrando AA, Lee W, Morris J.P.t., Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC, Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia, Science 306(5694) (2004) 269–71. 10.1126/science.1102160 [DOI] [PubMed] [Google Scholar]
[183].Forster R, Davalos-Misslitz AC, Rot A, CCR7 and its ligands: balancing immunity and tolerance, Nat Rev Immunol 8(5) (2008) 362–71. 10.1038/nri2297 [DOI] [PubMed] [Google Scholar]
[184].Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA, Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling, Cancer Cell 11(6) (2007) 526–38. 10.1016/j.ccr.2007.04.020 [DOI] [PubMed] [Google Scholar]
[185].Wilson JL, Burchell J, Grimshaw MJ, Endothelins induce CCR7 expression by breast tumor cells via endothelin receptor A and hypoxia-inducible factor-1, Cancer Res 66(24) (2006) 11802–7. 10.1158/0008-5472.CAN-06-1222 [DOI] [PubMed] [Google Scholar]
[186].Mori T, Kim J, Yamano T, Takeuchi H, Huang S, Umetani N, Koyanagi K, Hoon DS, Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells, Cancer Res 65(5) (2005) 1800–7. 10.1158/0008-5472.CAN-04-3531 [DOI] [PubMed] [Google Scholar]
[187].Chen Y, Stamatoyannopoulos G, Song CZ, Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro, Cancer Res 63(16) (2003) 4801–4. [PubMed] [Google Scholar]
[188].Wu S, Lu X, Zhang ZL, Lei P, Hu P, Wang M, Huang B, Xing W, Jiang XT, Liu HJ, Zhu ZG, Li WH, Zhu HF, Fu N, Shen GX, CC chemokine ligand 21 enhances the immunogenicity of the breast cancer cell line MCF-7 upon assistance of TLR2, Carcinogenesis 32(3) (2011) 296–304. 10.1093/carcin/bgq265 [DOI] [PubMed] [Google Scholar]
[189].Kobayashi D, Endo M, Ochi H, Hojo H, Miyasaka M, Hayasaka H, Regulation of CCR7-dependent cell migration through CCR7 homodimer formation, Sci Rep 7(1) (2017) 8536. 10.1038/s41598-017-09113-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
[190].Lu Y, Wang H, Mills GB, Targeting PI3K-AKT pathway for cancer therapy, Rev Clin Exp Hematol 7(2) (2003) 205–28. [PubMed] [Google Scholar]
[191].Rolin J, Maghazachi AA, Implications of chemokine receptors and inflammatory lipids in cancer, Immunotargets Ther 3 (2014) 9–18. 10.2147/ITT.S32049 [DOI] [PMC free article] [PubMed] [Google Scholar]
[192].Sotsios Y, Ward SG, Phosphoinositide 3-kinase: a key biochemical signal for cell migration in response to chemokines, Immunol Rev 177 (2000) 217–35. 10.1034/j.1600065x.2000.17712.x [DOI] [PubMed] [Google Scholar]
[193].Wang L, Zhang M, Zhu Y, Zhang X, Yang Y, Wang C, CCR4 Expression Is Associated With Poor Prognosis in Patients With Early Stage (pN0) Oral Tongue Cancer, J Oral Maxillofac Surg 77(2) (2019) 426–432. 10.1016/j.joms.2018.09.035 [DOI] [PubMed] [Google Scholar]
[194].Geller S, Hollmann TJ, Horwitz SM, Myskowski PL, Pulitzer M, C-C chemokine receptor 4 expression in CD8+ cutaneous T-cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment, Histopathology 76(2) (2020) 222–232. 10.1111/his.13960 [DOI] [PMC free article] [PubMed] [Google Scholar]
[195].Klein A, Sagi-Assif O, Meshel T, Telerman A, Izraely S, Ben-Menachem S, Bayry J, Marzese DM, Ohe S, Hoon DSB, Erez N, Witz IP, CCR4 is a determinant of melanoma brain metastasis, Oncotarget 8(19) (2017) 31079–31091. 10.18632/oncotarget.16076 [DOI] [PMC free article] [PubMed] [Google Scholar]
[196].Klein A, Sagi-Assif O, Izraely S, Meshel T, Pasmanik-Chor M, Nahmias C, Couraud PO, Erez N, Hoon DS, Witz IP, The metastatic microenvironment: Brain-derived soluble factors alter the malignant phenotype of cutaneous and brain-metastasizing melanoma cells, Int J Cancer 131(11) (2012) 2509–18. 10.1002/ijc.27552 [DOI] [PubMed] [Google Scholar]
[197].Jacquelot N, Duong CPM, Belz GT, Zitvogel L, Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers, Front Immunol 9 (2018) 2480. 10.3389/fimmu.2018.02480 [DOI] [PMC free article] [PubMed] [Google Scholar]
[198].Redmer T, Deciphering mechanisms of brain metastasis in melanoma - the gist of the matter, Mol Cancer 17(1) (2018) 106. 10.1186/s12943-018-0854-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
[199].Ou B, Zhao J, Guan S, Feng H, Wangpu X, Zhu C, Zong Y, Ma J, Sun J, Shen X, Zheng M, Lu A, CCR4 promotes metastasis via ERK/NF-kappaB/MMP13 pathway and acts downstream of TNF-alpha in colorectal cancer, Oncotarget 7(30) (2016) 47637–47649. 10.18632/oncotarget.10256 [DOI] [PMC free article] [PubMed] [Google Scholar]
[200].Mollica Poeta V, Massara M, Capucetti A, Bonecchi R, Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy, Front Immunol 10 (2019) 379. 10.3389/fimmu.2019.00379 [DOI] [PMC free article] [PubMed] [Google Scholar]
[201].Marcuzzi E, Angioni R, Molon B, Cali B, Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization, Int J Mol Sci 20(1) (2018). 10.3390/ijms20010096 [DOI] [PMC free article] [PubMed] [Google Scholar]
[202].Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, Taichman RS, Pienta KJ, Wang J, CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression, Cancer Metastasis Rev 29(4) (2010) 709–22. 10.1007/s10555-010-9256-x [DOI] [PMC free article] [PubMed] [Google Scholar]
[203].Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L, Shim H, Silencing of CXCR4 blocks breast cancer metastasis, Cancer Res 65(3) (2005) 967–71. [PMC free article] [PubMed] [Google Scholar]
[204].Salazar N, Carlson JC, Huang K, Zheng Y, Oderup C, Gross J, Jang AD, Burke TM, Lewen S, Scholz A, Huang S, Nease L, Kosek J, Mittelbronn M, Butcher EC, Tu H, Zabel BA, A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models, Mol Ther 26(5) (2018) 1354–1365. 10.1016/j.ymthe.2018.02.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
[205].Yu S, Duan J, Zhou Z, Pang Q, Wuyang J, Liu T, He X, Xinfa L, Chen Y, A critical role of CCR7 in invasiveness and metastasis of SW620 colon cancer cell in vitro and in vivo, Cancer Biol Ther 7(7) (2008) 1037–43. 10.4161/cbt.7.7.6065 [DOI] [PubMed] [Google Scholar]
[206].Chi BJ, Du CL, Fu YF, Zhang YN, Wang RW, Silencing of CCR7 inhibits the growth, invasion and migration of prostate cancer cells induced by VEGFC, Int J Clin Exp Pathol 8(10) (2015) 12533–40. [PMC free article] [PubMed] [Google Scholar]
[207].Smit MJ, Schlecht-Louf G, Neves M, den Bor JV, Penela P, Siderius M, Bachelerie F, Mayor F Jr., The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting, Annu Rev Pharmacol Toxicol (2020). 10.1146/annurev-pharmtox-010919-023340 [DOI] [PubMed] [Google Scholar]
[208].Bridger GJ, Skerlj RT, Hernandez-Abad PE, Bogucki DE, Wang Z, Zhou Y, Nan S, Boehringer EM, Wilson T, Crawford J, Metz M, Hatse S, Princen K, De Clercq E, Schols D, Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication, J Med Chem 53(3) (2010) 1250–60. 10.1021/jm901530b [DOI] [PubMed] [Google Scholar]
[209].Pernas S, Martin M, Kaufman PA, Gil-Martin M, Gomez Pardo P, Lopez-Tarruella S, Manso L, Ciruelos E, Perez-Fidalgo JA, Hernando C, Ademuyiwa FO, Weilbaecher K, Mayer I, Pluard TJ, Martinez Garcia M, Vahdat L, Perez-Garcia J, Wach A, Barker D, Fung S, Romagnoli B, Cortes J, Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial, Lancet Oncol 19(6) (2018) 812–824. 10.1016/S1470-2045(18)30147-5 [DOI] [PubMed] [Google Scholar]
[210].Shelke NB, Kadam R, Tyagi P, Rao VR, Kompella UB, Intravitreal Poly(L-lactide) Microparticles Sustain Retinal and Choroidal Delivery of TG-0054, a Hydrophilic Drug Intended for Neovascular Diseases, Drug Deliv Transl Res 1(1) (2011) 76–90. 10.1007/s13346-010-0009-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
[211].Skerlj RT, Bridger GJ, Kaller A, McEachern EJ, Crawford JB, Zhou Y, Atsma B, Langille J, Nan S, Veale D, Wilson T, Harwig C, Hatse S, Princen K, De Clercq E, Schols D, Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication, J Med Chem 53(8) (2010) 3376–88. 10.1021/jm100073m [DOI] [PubMed] [Google Scholar]
[212].Micallef IN, Stiff PJ, Nademanee AP, Maziarz RT, Horwitz ME, Stadtmauer EA, Kaufman JL, McCarty JM, Vargo R, Cheverton PD, Struijs M, Bolwell B, DiPersio JF, Plerixafor Plus Granulocyte Colony-Stimulating Factor for Patients with Non-Hodgkin Lymphoma and Multiple Myeloma: Long-Term Follow-Up Report, Biol Blood Marrow Transplant 24(6) (2018) 1187–1195. 10.1016/j.bbmt.2018.01.039 [DOI] [PMC free article] [PubMed] [Google Scholar]
[213].Pham K, Luo D, Siemann DW, Law BK, Reynolds BA, Hothi P, Foltz G, Harrison JK, VEGFR inhibitors upregulate CXCR4 in VEGF receptor-expressing glioblastoma in a TGFbetaR signaling-dependent manner, Cancer Lett 360(1) (2015) 60–7. 10.1016/j.canlet.2015.02.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
[214].Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D, Rubin JB, Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo, Cancer Res 67(2) (2007) 651–8. 10.1158/0008-5472.CAN-06-2762 [DOI] [PubMed] [Google Scholar]
[215].Peng SB, Zhang X, Paul D, Kays LM, Gough W, Stewart J, Uhlik MT, Chen Q, Hui YH, Zamek-Gliszczynski MJ, Wijsman JA, Credille KM, Yan LZ, Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models, Mol Cancer Ther 14(2) (2015) 480–90. 10.1158/1535-7163.MCT-14-0850 [DOI] [PubMed] [Google Scholar]
[216].Ling X, Spaeth E, Chen Y, Shi Y, Zhang W, Schober W, Hail N Jr., Konopleva M, Andreeff M, The CXCR4 antagonist AMD3465 regulates oncogenic signaling and invasiveness in vitro and prevents breast cancer growth and metastasis in vivo, PLoS One 8(3) (2013) e58426. 10.1371/journal.pone.0058426 [DOI] [PMC free article] [PubMed] [Google Scholar]
[217].Galsky MD, Vogelzang NJ, Conkling P, Raddad E, Polzer J, Roberson S, Stille JR, Saleh M, Thornton D, A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer, Clin Cancer Res 20(13) (2014) 3581–8. 10.1158/1078-0432.CCR-13-2686 [DOI] [PubMed] [Google Scholar]
[218].Bobkov V, Arimont M, Zarca A, De Groof TWM, van der Woning B, de Haard H, Smit MJ, Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3, Mol Pharmacol 96(6) (2019) 753–764. 10.1124/mol.119.116954 [DOI] [PubMed] [Google Scholar]
[219].Bobkov V, Zarca AM, Van Hout A, Arimont M, Doijen J, Bialkowska M, Toffoli E, Klarenbeek A, van der Woning B, van der Vliet HJ, Van Loy T, de Haard H, Schols D, Heukers R, Smit MJ, Nanobody-Fc constructs targeting chemokine receptor CXCR4 potently inhibit signaling and CXCR4-mediated HIV-entry and induce antibody effector functions, Biochem Pharmacol 158 (2018) 413–424. 10.1016/j.bcp.2018.10.014 [DOI] [PubMed] [Google Scholar]
[220].Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ, A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development, J Exp Med 203(9) (2006) 2201–13. 10.1084/jem.20052144 [DOI] [PMC free article] [PubMed] [Google Scholar]
[221].Goguet-Surmenian E, Richard-Fiardo P, Guillemot E, Benchetrit M, Gomez-Brouchet A, Buzzo P, Karimdjee-Soilihi B, Alemanno P, Michiels JF, Schmid-Alliana A, Schmid-Antomarchi H, CXCR7-mediated progression of osteosarcoma in the lungs, Br J Cancer 109(6) (2013) 1579–85. 10.1038/bjc.2013.482 [DOI] [PMC free article] [PubMed] [Google Scholar]
[222].Luo Y, Azad AK, Karanika S, Basourakos SP, Zuo X, Wang J, Yang L, Yang G, Korentzelos D, Yin J, Park S, Zhang P, Campbell JJ, Schall TJ, Cao G, Li L, Thompson TC, Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models, Int J Cancer 142(10) (2018) 2163–2174. 10.1002/ijc.31237 [DOI] [PMC free article] [PubMed] [Google Scholar]
[223].Rafiei S, Gui B, Wu J, Liu XS, Kibel AS, Jia L, Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer, Mol Cancer Res 17(1) (2019) 263–276. 10.1158/1541-7786.MCR-18-0412 [DOI] [PMC free article] [PubMed] [Google Scholar]
[224].Walters MJ, Ebsworth K, Berahovich RD, Penfold ME, Liu SC, Al Omran R, Kioi M, Chernikova SB, Tseng D, Mulkearns-Hubert EE, Sinyuk M, Ransohoff RM, Lathia JD, Karamchandani J, Kohrt HE, Zhang P, Powers JP, Jaen JC, Schall TJ, Merchant M, Recht L, Brown JM, Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats, Br J Cancer 110(5) (2014) 1179–88. 10.1038/bjc.2013.830 [DOI] [PMC free article] [PubMed] [Google Scholar]
[225].Hartmann TN, Grabovsky V, Pasvolsky R, Shulman Z, Buss EC, Spiegel A, Nagler A, Lapidot T, Thelen M, Alon R, A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells, J Leukoc Biol 84(4) (2008) 1130–40. 10.1189/jlb.0208088 [DOI] [PubMed] [Google Scholar]
[226].Azad BB, Chatterjee S, Lesniak WG, Lisok A, Pullambhatla M, Bhujwalla ZM, Pomper MG, Nimmagadda S, A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts, Oncotarget 7(11) (2016) 12344–58. 10.18632/oncotarget.7111 [DOI] [PMC free article] [PubMed] [Google Scholar]
[227].De Groof TWM, Bobkov V, Heukers R, Smit MJ, Nanobodies: New avenues for imaging, stabilizing and modulating GPCRs, Mol Cell Endocrinol 484 (2019) 15–24. 10.1016/j.mce.2019.01.021 [DOI] [PubMed] [Google Scholar]
[228].Kim SJ, Shin JY, Lee KD, Bae YK, Sung KW, Nam SJ, Chun KH, MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7, Breast Cancer Res 14(1) (2012) R14. 10.1186/bcr3098 [DOI] [PMC free article] [PubMed] [Google Scholar]
[229].Otero C, Eisele PS, Schaeuble K, Groettrup M, Legler DF, Distinct motifs in the chemokine receptor CCR7 regulate signal transduction, receptor trafficking and chemotaxis, J Cell Sci 121(Pt 16) (2008) 2759–67. 10.1242/jcs.029074 [DOI] [PubMed] [Google Scholar]
[230].Stein JV, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn MD, Matsuzawa A, Quackenbush EJ, Dorf ME, von Andrian UH, The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules, J Exp Med 191(1) (2000) 61–76. 10.1084/jem.191.1.61 [DOI] [PMC free article] [PubMed] [Google Scholar]
[231].Yang SC, Hillinger S, Riedl K, Zhang L, Zhu L, Huang M, Atianzar K, Kuo BY, Gardner B, Batra RK, Strieter RM, Dubinett SM, Sharma S, Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity, Clin Cancer Res 10(8) (2004) 2891–901. 10.1158/1078-0432.ccr-03-0380 [DOI] [PubMed] [Google Scholar]
[232].Lu L, Tao H, Chang AE, Hu Y, Shu G, Chen Q, Egenti M, Owen J, Moyer JS, Prince ME, Huang S, Wicha MS, Xia JC, Li Q, Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells, Oncoimmunology 4(3) (2015) e990767. 10.4161/2162402X.2014.990767 [DOI] [PMC free article] [PubMed] [Google Scholar]
[233].Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG, Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses, Cancer Res 73(3) (2013) 1128–41. 10.1158/0008-5472.CAN-12-2731 [DOI] [PMC free article] [PubMed] [Google Scholar]
[234].Cullis J, Siolas D, Avanzi A, Barui S, Maitra A, Bar-Sagi D, Macropinocytosis of Nabpaclitaxel Drives Macrophage Activation in Pancreatic Cancer, Cancer Immunol Res 5(3) (2017) 182–190. 10.1158/2326-6066.CIR-16-0125 [DOI] [PMC free article] [PubMed] [Google Scholar]
[235].Nywening TM, Wang-Gillam A, Sanford DE, Belt BA, Panni RZ, Cusworth BM, Toriola AT, Nieman RK, Worley LA, Yano M, Fowler KJ, Lockhart AC, Suresh R, Tan BR, Lim KH, Fields RC, Strasberg SM, Hawkins WG, DeNardo DG, Goedegebuure SP, Linehan DC, Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial, Lancet Oncol 17(5) (2016) 651–62. 10.1016/S1470-2045(16)00078-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
[236].Li X, Yao W, Yuan Y, Chen P, Li B, Li J, Chu R, Song H, Xie D, Jiang X, Wang H, Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma, Gut 66(1) (2017) 157–167. 10.1136/gutjnl-2015-310514 [DOI] [PubMed] [Google Scholar]
[237].Yao W, Ba Q, Li X, Li H, Zhang S, Yuan Y, Wang F, Duan X, Li J, Zhang W, Wang H, A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer, EBioMedicine 22 (2017) 58–67. 10.1016/j.ebiom.2017.07.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
[238].Bonapace L, Coissieux MM, Wyckoff J, Mertz KD, Varga Z, Junt T, Bentires-Alj M, Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis, Nature 515(7525) (2014) 130–3. 10.1038/nature13862 [DOI] [PubMed] [Google Scholar]
[239].Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E, Beatty GL, Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma, Clin Cancer Res 23(1) (2017) 137–148. 10.1158/1078-0432.CCR-16-0870 [DOI] [PMC free article] [PubMed] [Google Scholar]
[240].Mogamulizumab Tops Standard of Care for CTCL, Cancer Discov 8(2) (2018) OF1. 10.1158/2159-8290.CD-NB2018-001 [DOI] [PubMed] [Google Scholar]
[241].Fuji S, Utsunomiya A, Inoue Y, Miyagi T, Owatari S, Sawayama Y, Moriuchi Y, Choi I, Shindo T, Yoshida SI, Yamasaki S, Yamaguchi T, Fukuda T, Outcomes of patients with relapsed aggressive adult T-cell leukemia-lymphoma: clinical effectiveness of anti-CCR4 antibody and allogeneic hematopoietic stem cell transplantation, Haematologica 103(5) (2018) e211–e214. 10.3324/haematol.2017.184564 [DOI] [PMC free article] [PubMed] [Google Scholar]
[242].Perera LP, Zhang M, Nakagawa M, Petrus MN, Maeda M, Kadin ME, Waldmann TA, Perera PY, Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies, Am J Hematol 92(9) (2017) 892–901. 10.1002/ajh.24794 [DOI] [PMC free article] [PubMed] [Google Scholar]
[243].Berlato C, Khan MN, Schioppa T, Thompson R, Maniati E, Montfort A, Jangani M, Canosa M, Kulbe H, Hagemann UB, Duncan AR, Fletcher L, Wilkinson RW, Powles T, Quezada SA, Balkwill FR, A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer, J Clin Invest 127(3) (2017) 801–813. 10.1172/JCI82976 [DOI] [PMC free article] [PubMed] [Google Scholar]
[244].Fuji S, Shindo T, Friend or foe? Mogamulizumab in allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma, Stem Cell Investig 3 (2016) 70. 10.21037/sci.2016.09.13 [DOI] [PMC free article] [PubMed] [Google Scholar]
[245].Beziaud L, Boullerot L, Tran T, Mansi L, Marie-Joseph EL, Ravel P, Johannes L, Bayry J, Tartour E, Adotevi O, Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy, Int J Cancer 143(11) (2018) 3008–3018. 10.1002/ijc.31842 [DOI] [PubMed] [Google Scholar]
[246].Zlotnik A, Burkhardt AM, Homey B, Homeostatic chemokine receptors and organ-specific metastasis, Nat Rev Immunol 11(9) (2011) 597–606. 10.1038/nri3049 [DOI] [PubMed] [Google Scholar]
[247].Mukaida N, Sasaki S, Baba T, Chemokines in cancer development and progression and their potential as targeting molecules for cancer treatment, Mediators Inflamm 2014 (2014) 170381. 10.1155/2014/170381 [DOI] [PMC free article] [PubMed] [Google Scholar]
[248].Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R, Beider K, Avniel S, Kasem S, Galun E, Peled A, Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis, FASEB J 18(11) (2004) 1240–2. 10.1096/fj.03-0935fje [DOI] [PubMed] [Google Scholar]
[249].Arya M, Patel HR, McGurk C, Tatoud R, Klocker H, Masters J, Williamson M, The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis, J Exp Ther Oncol 4(4) (2004) 291–303. [PubMed] [Google Scholar]
[250].Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T, Chen Y, Han X, Wu K, The CXCL8-CXCR1/2 pathways in cancer, Cytokine Growth Factor Rev 31 (2016) 61–71. 10.1016/j.cytogfr.2016.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
[251].Du L, Han XG, Tu B, Wang MQ, Qiao H, Zhang SH, Fan QM, Tang TT, CXCR1/Akt signaling activation induced by mesenchymal stem cell-derived IL-8 promotes osteosarcoma cell anoikis resistance and pulmonary metastasis, Cell Death Dis 9(7) (2018) 714. 10.1038/s41419-018-0745-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
[252].Wu S, Saxena S, Varney ML, Singh RK, CXCR1/2 Chemokine Network Regulates Melanoma Resistance to Chemotherapies Mediated by NF-kappaB, Curr Mol Med 17(6) (2017) 436–449. 10.2174/1566524018666171219100158 [DOI] [PubMed] [Google Scholar]
[253].O’Hayre M, Salanga CL, Handel TM, Allen SJ, Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment, Biochem J 409(3) (2008) 635–49. 10.1042/BJ20071493 [DOI] [PubMed] [Google Scholar]
[254].Nurnberg W, Tobias D, Otto F, Henz BM, Schadendorf D, Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma, J Pathol 189(4) (1999) 546–51. 10.1002/(SICI)1096-9896(199912)189:4<546::AID-PATH487>3.0.CO;2-L [DOI] [PubMed] [Google Scholar]
[255].Scheibenbogen C, Mohler T, Haefele J, Hunstein W, Keilholz U, Serum interleukin-8 (IL-8) is elevated in patients with metastatic melanoma and correlates with tumour load, Melanoma Res 5(3) (1995) 179–81. 10.1097/00008390-199506000-00006 [DOI] [PubMed] [Google Scholar]
[256].Wu FY, Ou ZL, Feng LY, Luo JM, Wang LP, Shen ZZ, Shao ZM, Chemokine decoy receptor d6 plays a negative role in human breast cancer, Mol Cancer Res 6(8) (2008) 1276–88. 10.1158/1541-7786.MCR-07-2108 [DOI] [PubMed] [Google Scholar]
[257].Kawada K, Sonoshita M, Sakashita H, Takabayashi A, Yamaoka Y, Manabe T, Inaba K, Minato N, Oshima M, Taketo MM, Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes, Cancer Res 64(11) (2004) 4010–7. 10.1158/0008-5472.CAN-03-1757 [DOI] [PubMed] [Google Scholar]
[258].Ma X, Norsworthy K, Kundu N, Rodgers WH, Gimotty PA, Goloubeva O, Lipsky M, Li Y, Holt D, Fulton A, CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model, Mol Cancer Ther 8(3) (2009) 490–8. 10.1158/1535-7163.MCT-08-0485 [DOI] [PubMed] [Google Scholar]
[259].Vandercappellen J, Van Damme J, Struyf S, The role of CXC chemokines and their receptors in cancer, Cancer Lett 267(2) (2008) 226–44. 10.1016/j.canlet.2008.04.050 [DOI] [PubMed] [Google Scholar]
[260].Shin SY, Lee DH, Lee J, Choi C, Kim JY, Nam JS, Lim Y, Lee YH, C-C motif chemokine receptor 1 (CCR1) is a target of the EGF-AKT-mTOR-STAT3 signaling axis in breast cancer cells, Oncotarget 8(55) (2017) 94591–94605. 10.18632/oncotarget.21813 [DOI] [PMC free article] [PubMed] [Google Scholar]
[261].Li JY, Ou ZL, Yu SJ, Gu XL, Yang C, Chen AX, Di GH, Shen ZZ, Shao ZM, The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer, Breast Cancer Res Treat 131(3) (2012) 837–48. 10.1007/s10549-011-1502-6 [DOI] [PubMed] [Google Scholar]
[262].Stoll G, Pol J, Soumelis V, Zitvogel L, Kroemer G, Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts, Oncoimmunology 7(10) (2018) e1484980. 10.1080/2162402X.2018.1484980 [DOI] [PMC free article] [PubMed] [Google Scholar]
[263].Boyle ST, Faulkner JW, McColl SR, Kochetkova M, The chemokine receptor CCR6 facilitates the onset of mammary neoplasia in the MMTV-PyMT mouse model via recruitment of tumor-promoting macrophages, Mol Cancer 14 (2015) 115. 10.1186/s12943-015-0394-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
[264].Takanami I, Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis, Int J Cancer 105(2) (2003) 186–9. 10.1002/ijc.11063 [DOI] [PubMed] [Google Scholar]
[265].Amersi FF, Terando AM, Goto Y, Scolyer RA, Thompson JF, Tran AN, Faries MB, Morton DL, Hoon DS, Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine, Clin Cancer Res 14(3) (2008) 638–45. 10.1158/1078-0432.CCR-07-2025 [DOI] [PMC free article] [PubMed] [Google Scholar]
[266].Singh R, Stockard CR, Grizzle WE, Lillard JW Jr., Singh S, Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer, Int J Oncol 39(2) (2011) 373–81. 10.3892/ijo.2011.1059 [DOI] [PMC free article] [PubMed] [Google Scholar]
[267].Lazennec G, Richmond A, Chemokines and chemokine receptors: new insights into cancer-related inflammation, Trends Mol Med 16(3) (2010) 133–44. 10.1016/j.molmed.2010.01.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
[268].Celesti G, Di Caro G, Bianchi P, Grizzi F, Marchesi F, Basso G, Rahal D, Delconte G, Catalano M, Cappello P, Roncalli M, Zerbi A, Montorsi M, Novelli F, Mantovani A, Allavena P, Malesci A, Laghi L, Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis, Br J Cancer 109(9) (2013) 2424–33. 10.1038/bjc.2013.565 [DOI] [PMC free article] [PubMed] [Google Scholar]
[269].Marchesi F, Piemonti L, Fedele G, Destro A, Roncalli M, Albarello L, Doglioni C, Anselmo A, Doni A, Bianchi P, Laghi L, Malesci A, Cervo L, Malosio M, Reni M, Zerbi A, Di Carlo V, Mantovani A, Allavena P, The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma, Cancer Res 68(21) (2008) 9060–9. 10.1158/0008-5472.CAN-08-1810 [DOI] [PubMed] [Google Scholar]
[270].Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N, Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells, Nat Biotechnol 25(8) (2007) 911–20. 10.1038/nbt1323 [DOI] [PubMed] [Google Scholar]
[271].Shulby SA, Dolloff NG, Stearns ME, Meucci O, Fatatis A, CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells, Cancer Res 64(14) (2004) 4693–8. 10.1158/0008-5472.CAN-03-3437 [DOI] [PubMed] [Google Scholar]
[272].Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A, Broglio K, Spano JP, Combadiere C, Bucana C, Soria JC, Cristofanilli M, Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer, Ann Oncol 17(6) (2006) 945–51. 10.1093/annonc/mdl053 [DOI] [PubMed] [Google Scholar]
[273].Zabel BA, Wang Y, Lewen S, Berahovich RD, Penfold ME, Zhang P, Powers J, Summers BC, Miao Z, Zhao B, Jalili A, Janowska-Wieczorek A, Jaen JC, Schall TJ, Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands, J Immunol 183(5) (2009) 3204–11. 10.4049/jimmunol.0900269 [DOI] [PubMed] [Google Scholar]

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