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. 2013 Nov 4;2(12):946–952. doi: 10.5966/sctm.2013-0055

Concise Review: Growth Differentiation Factor 15 in Pathology: A Clinical Role?

Jill Corre a,b,c, Benjamin Hébraud a,d, Philippe Bourin e,✉
PMCID: PMC3841089  PMID: 24191265

Increased blood concentration of GDF15 is associated with numerous pathological conditions, but the biological significance underlying these observations is far from clear. GDF15 seems to be an integrative signal in pathologic conditions, giving information on severity of disease, but its effectiveness in classifying patients to modulate treatment remains to be shown. This review article surveys the state of current knowledge about GDF15.

Keywords: Cancer, Clinical translation, Drug target, Malignancy

Abstract

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor β family discovered in a broad range of cells, as indicated by the diversity of its nomenclature. However, the only tissue that expresses a high amount of GDF15 in the physiologic state is placenta. GDF15 is easily detected in blood, and its concentration varies with age. In fact, increased blood concentration of GDF15 is associated with numerous pathological conditions. However, the biological significance underlying these observations is far from clear. GDF15 could have a positive or negative role depending on the state of cells or their environment. Furthermore, study of its biology is hampered by lack of knowledge of its receptor and thus the signaling pathways that drive its action. GDF15 seems to be an integrative signal in pathologic conditions, giving information on severity of disease. Its effectiveness in classifying patients to modulate treatment remains to be shown. Development of therapeutic interventions with GDF15 or anti-GDF15 agents remains difficult until we uncover the mechanism that drives its activity.

Introduction

Growth differentiation factor 15 (GDF15), also termed macrophage inhibitory cytokine 1, was first isolated from a cDNA library enriched for macrophage-associated genes obtained from the U937 cell line. It was described as a divergent member of the human transforming growth factor β (TGF-β) superfamily [1]. The GDF15 gene is localized on chromosome 19p12–13.1; the DNA sequence is 2,746 base pairs and encompasses two exons separated by an intron. GDF15 is secreted as a 40-kDa propeptide that is cleaved in the endoplasmic reticulum to release a 25-kDa active circulating dimeric protein [2]. The propeptide can also be secreted and associated with extracellular matrix, for latent storage of the protein in stroma [3]. Proinflammatory cytokines such as tumor necrosis factor α or interleukin 6 (IL-6) induce the mRNA expression of GDF15 in activated macrophages, which suggests that GDF15 could function as an autocrine inhibitor during the inflammatory response [1, 4]. Subsequently, GDF15 was found to have broad activity, as indicated by the diversity of its nomenclature [5].

The placenta is the only tissue that expresses a large amount of GDF15 under physiological conditions. GDF15 is localized both in placenta and fetal membranes, which suggests a role at the maternal-fetal interface [6]. It probably promotes fetal survival by suppressing the maternal production of proinflammatory cytokines within the uterus and/or allowing the immunotolerance of the semiallogeneic fetus. Interestingly, GDF15 has been suggested to have immunosuppressive characteristics by inhibiting proliferation of peripheral blood mononuclear cells and inducing the expression of forkhead box protein 3 in CD4+CD25+ cells [7]. Pregnancy features high serum levels of GDF15, with a progressive increase from a normal level to peak in the third trimester [8]. Hence, low serum level of GDF15 between 6 and 13 weeks' gestation may predict miscarriage [9]. GDF15 expression can increase in response to diverse cellular stress signals, such as hypoxia/anoxia, inflammation, acute tissue injuries, and the tumor process. Here, we review the involvement of GDF15 in pathologic conditions (summarized in Fig. 1) and draw some perspectives for clinical applications.

Figure 1.

Figure 1.

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Involvement of GDF15 in pathologic disease. GDF15 expression is associated with numerous pathological situations and seems to be an integrative signal in pathologic conditions, giving information on severity of disease. Abbreviation: GDF15, growth differentiation factor 15.

GDF15 in Pathologic Conditions: A Probable Marker of Disease and Mortality

GDF15 is associated with all-cause mortality, as a general marker of diseases. In 2010, Wiklund et al. reported on their study of 815 Swedish males 46–80 years old and, in parallel, an independent cohort of 324 twins [10]. In the male cohort, the serum concentration of GDF15 predicted mortality, whatever the cause. Although the GDF15 plasma concentration was correlated with age of subjects and their smoking history, a high GDF15 level remained predictive of overall mortality on multivariate analysis, independent of age, body mass index (BMI), and smoking. The relationship between all-cause mortality and GDF15 plasma level was confirmed in the twin cohort and was independent of genetic background, even after adjustment for telomere length and levels of IL-6 and C-reactive protein (CRP) [10]. These findings were confirmed by another longitudinal study reported in 2011 [11] of community-dwelling older adults followed for at least 11 years. Among 1,391 subjects without cardiovascular disease, the plasma concentration of GDF15 was correlated with time to death. GDF15 plasma concentration was a stronger predictor than were NT-proBNP and CRP levels. Thus, these two studies suggest the interest of plasma concentration of GDF15 as a prognostic factor in various diseases.

GDF15 in Cancer

Although GDF15 has been described as belonging to a series of 20 biomarkers that best define the malignant phenotype of numerous tumors [12], understanding its biological role in cancer is still a challenge [5, 13]. Like the other members of the TGF-β superfamily, GDF15 can have opposite effects depending on cellular context, disease stage, or microenvironment. Some studies have documented its antitumorigenic activity, and others have shown a protumorigenic role. In fact, these apparently paradoxical data could be explained by a dual role of GDF15 in cancer progression: inhibition of carcinogenesis in normal tissue at early stages of tumor development and promotion of tumor at late stages of the disease [2]. GDF15 can induce pleiotropic effects in cancer (summarized in Fig. 2) by modulating cancer cell proliferation and chemoprotection but also the tumoral microenvironment (angiogenesis, invasion and metastasis processes, immunomodulation), as well as more unexpected processes, such as cancer-induced anorexia.

Figure 2.

Figure 2.

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Role of GDF15 in the tumor process. Like the other members of the transforming growth factor β superfamily, GDF15 can have opposite effects depending on cellular context, disease stage, or microenvironment (e.g., protumoral or antitumoral). However, the protumoral effects seem to prevail. Abbreviation: GDF15, growth differentiation factor 15.

Expression of GDF15 in Cancers

GDF15 expression and secretion are enhanced in many malignant tissue and cancer cell lines (notably prostate, colorectal, gastric, and pancreatic cancers; oral squamous carcinoma; melanoma; and glioma) as compared with their normal tissues or cells [14–21]. GDF15 was not documented in hematological malignancies as compared with solid tumors. A few years ago, we demonstrated that the only long-lived cells of the bone-marrow microenvironment, mesenchymal stem cells (MSCs), show specific abnormalities in multiple myeloma (MM) [22]. In particular, both GDF15 mRNA and secreted protein levels were fourfold higher in MSCs from patients with myeloma at diagnosis than in normal MSCs. However, as compared with its production in solid tumors, GDF15 was not produced by malignant myeloma cells [22].

Antitumoral Bioactivity of GDF15

The expression of GDF15 in several cancer cell lines results in cell growth arrest and apoptosis, which suggests that GDF15 may have antitumorigenic activity. For instance, GDF15 inhibits growth in MCF-7 human breast cancer cells [23]. Furthermore, transgenic mice ubiquitously expressing human GDF15 were resistant to development of chemically and genetically induced intestinal tumors [24]. GDF15 is an important downstream target of the major tumor suppressor p53 [25] as well as early growth response 1 [26] and Akt/GSK-3β [27]. The induction of its expression by nonsteroidal anti-inflammatory drugs has been proposed to explain the cyclooxygenase-independent prevention effect of these drugs on digestive-system cancer [24]. These studies suggest that GDF15 induces cell growth arrest and apoptosis, but its upregulation in human cancers favors a protumoral role.

Protumoral Activity of GDF15

Proliferation, Survival, and Chemoprotection of Cancer Cells

Silencing GDF15 with RNA interference reduced the proliferation of malignant glioma cells [20], thus demonstrating the GDF15 contribution to tumor growth. We found that exogenous recombinant GDF15 increased the survival of stroma-dependent myeloma cells, including fresh primary myeloma cells, in serum-free culture [28]. Because we had previously reported that proliferation of myeloma cells was greater when cultivated with MSCs from patients with myeloma than normal MSCs, we wondered whether the overproduction of GDF15 by myeloma MSCs was involved. Indeed, when myeloma MSCs were transfected with short hairpin RNA targeting GDF15, the overproliferation of myeloma cells was significantly reduced [28].

Prostate cancer cell lines such as DU-145 or PC3 with overexpression of GDF15 or exposure to exogenous recombinant GDF15 showed resistance to docetaxel and mitoxantrone [29]. GDF15 conferred resistance to melphalan, bortezomib, and lenalidomide in the MOLP-6 and MM1.S myeloma cell lines [28]. Several mechanisms have been proposed to explain the protumorigenic activity of GDF15 in cancer cells, notably through activation of important survival signaling pathways. GDF15 can induce activation of Akt and the extracellular signal-related kinase (ERK) pathway [30–32]. Recently, Park et al. reported that GDF15 transactivates ErbB family receptors by activating Src in SK-BR-3 breast cancer cells [19]. In myeloma, bioactivity of GDF15 in cancer cells is related to an Akt-dependent mechanism but is independent of ERK1/2 and Src pathways [28].

Although GDF15 has been described in many solid tumors for almost 10 years, its receptor is still unknown. There is some evidence of Smad pathway activation, suggesting GDF15 may act through TGF-β receptor superfamily pathways [33]. Recently, GDF15 has been implicated in a CCR2/TGF-β RII-dependent mechanism [34] and shown to induce the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells [32]. In addition to its direct bioactivity in cancer cells, GDF15 has often been described to modulate the tumoral microenvironment.

Angiogenesis

Knockdown of GDF15 expression with short hairpin RNA decreased the tumorigenicity of three melanoma cell lines, D04, A2058, and C32, in a mouse xenograft model but had no direct effect on growth in vitro, which suggests a function other than growth control [18]. A more recent study explained this discrepancy between GDF15 bioactivity in vitro and in vivo and showed that inhibition of GDF15 expression retards melanoma vasculature development [35]. Of note, GDF15-induced anoxia has been suggested to exert antiangiogenic activity because its ectopic expression in a LN-Z308 glioblastoma cell line abolished its tumorigenicity in nude mice [36]. Thus, GDF15 can have opposite effects depending on the biological context.

Migration

GDF15 contributes to the malignant progression of various cancers, notably to promoting the ability of tumor cells to invade their surrounding environment. Overexpression of GDF15 or stimulation by exogenous recombinant GDF15 induced the invasiveness of the gastric cancer cell line SNU-216 by upregulating the urokinase-type plasminogen activator system that allows extracellular matrix degradation [21]. In prostate cancer cell line DU-145, GDF15 reduced cell adhesion by downregulating RhoE and catenin-δ1, which suggests a role in tumor dissemination [37]. More recently, GDF15 increased the motility of prostate cancer PC-3 cells via actin reorganization through a focal adhesion kinase-Ras homologous A (FAK-RhoA) signaling pathway [38].

Bone Lysis

GDF15 has a slight and Toll-like receptor 9-independent stimulatory effect on differentiation of both osteoblasts (early precursors) and osteoclasts in vitro; in contrast, in an intratibial model of bone metastasis, GDF15 overexpression in DU-145 prostate cells was associated only with osteoclast activation, which suggests a GDF15-induced uncoupling of osteoclast and osteoblast activity [39]. In a recent study, not with tumoral but ischemic bone, GDF15 was described as a key candidate factor secreted from osteocytes under hypoxia that acts as an osteoclastic factor through concomitant facilitation of phosphorylation of both p65 and inhibitory κB in the presence of receptor activator of nuclear factor-κB ligand [40]. Interestingly, in multiple myeloma, activation of bone resorption and inhibition of bone formation led to typical osteolytic lesions. The role of a hypoxic niche via hypoxia-inducible factor 1 (HIF-1) and HIF-2 in myeloma is largely debated, in particular on the potential link with abnormal angiogenesis in bone marrow of patients [41]. GDF15 could be the link between hypoxia and osteolytic lesions in myeloma. Indeed, we found significantly higher plasma concentration of GDF15 in patients with than without osteolytic lesions [28]. Further studies are needed to investigate the potential role of GDF15 as an osteoclast activating factor in myeloma, and to consider therapeutic targeting of GDF15 in order to decrease osteolytic lesions in patients.

Immunomodulation

Increased serum level of GDF15 is associated with decreased tumor lymphocyte infiltration in colon cancer, so GDF15 could be an inhibitor of the antitumor immune response by inhibiting leukocyte recruitment [42]. In parallel, in malignant glioma, GDF15 has been suggested to contribute to the immune escape of the tumor; the depletion of glioma-derived GDF15 enhances the susceptibility of mouse glioma cells toward syngeneic natural killer cells and splenocytes. This situation resulted in reduced in vivo tumorigenicity and increased T-cell infiltration of GDF15-deficient glioma cells in syngeneic mice [20]. In myeloma, GDF15 oversecreted in the tumoral bone marrow microenvironment may dampen immune mechanisms controlling the minimal residual disease. However, we did not find any bioactivity of recombinant GDF15 in proliferation of natural killer cells, cytotoxicity, or interferon γ production (personal data), which suggests a potential indirect effect of GDF15 rendering myeloma cells less sensitive to natural killer cell lysis.

Cancer-Induced Anorexia

GDF15 transgenic mice show reduced body weight [24]. These data have been confirmed by Johnen et al., who demonstrated that tumor-induced anorexia and weight loss are mediated by GDF15 through central mechanisms that implicate the hypothalamic TGF-β receptor II, ERK1 and ERK2, signal transducer and activator of transcription-3, neuropeptide Y, and pro-opiomelanocortin [31]. Interestingly, in normal subjects, GDF15 was positively correlated with adiponectin level and negatively with BMI and body fat mass [43].

Prognostic Biomarker

GDF15 concentration is notably increased in serum of patients with colorectal, pancreatic, and prostate cancers; glioma; ovarian and endometrial cancers; and melanoma [20, 42, 44–48]. The main interest of measuring GDF15 level in blood from patients is its association with advanced stages of the disease and/or prognosis. For instance, increased serum level of GDF15 is associated with progression of metastatic prostate cancer [44]. In metastatic melanoma, GDF15 concentration is higher in patients with unresected stage IV disease than resected stage I/II disease, so GDF15 may be used to monitor disease recurrence [48]. We recently showed an association of plasma concentration of GDF15 in patients with newly diagnosed myeloma with initial disease parameters and patient survival [28].

Areas Other Than Cancer

Erythropoiesis

GDF15 appeared as one of the most overexpressed genes in a transcriptomic study of erythroblasts from CD34+ hematopoietic stem cells obtained on day 7 and day 14 culture and may have a clear role in erythroid niche [49]. Those data led the authors to evaluate GDF15 levels in different settings, especially in the situation of ineffective erythropoiesis: the thalassemic patients. The authors found excessively increased amounts of GDF15 for those patients, who are also known to be affected by iron overload because of overexpression of ferroportine in enterocytes due to a lack of hepcidin [49]. The authors showed, using an in vitro system of hepatocytes (origin of hepcidin), that adding GDF15 was able to decrease mRNA production of hepcidin possibly via a Smad2/3-Smad4 signaling. Other studies have documented GDF15 overexpression linked to ineffective erythropoiesis, such as congenital dyserythropoietic anemia type 1 [50], refractory anemia with ring sideroblasts [51], and, to a lesser extent, pyruvate kinase deficiency [52].

In patients with myeloma, we found a strong negative correlation between GDF15 plasma concentration and hemoglobin level [28]; however, recombinant human GDF15 had a slight inhibition effect on hematopoiesis in vitro and not only on erythropoiesis (personal data). Interestingly, a recent work by Bruns et al. [53] showed functional impairment of hematopoietic stem and progenitor cells in myeloma that was specifically related to the myeloma microenvironment and depended on TGF-β signaling. As the use of erythropoietin is associated with thromboembolism risk and shorter survival, it should be interesting to elucidate the mechanism of anemia in MM; especially microenvironment/GDF15-mediated anemia in order to provide therapeutic issues to reverse this comorbidity.

Cardiology

We found 85 of 388 articles about GDF15 (as reported in PubMed, February 2013) that were based on cardiovascular research from bench to bedside. This situation shows the great interest of the cardiovascular community in this molecule since the first paper published in this field, in 2002, by Brown et al. [54]. This study compared the baseline plasma concentration of GDF15 in women who experienced a cardiovascular event during a 4-year follow-up and in age- and smoking status-matched women who remained healthy during this period. The risk of experiencing a cardiovascular event increased with increased baseline plasma concentration of GDF15. The risk remained significant after adjustment for classic cardiovascular risk factors. Following this first paper, the association of elevated plasma concentration of GDF15 with outcomes in various cardiovascular situations has been intensively studied. Clinicians at the Hannover Medical School devised an immunoradiometric assay to measure GDF15 concentration in plasma and showed a high level of GDF15 associated with poor prognosis in patients with chronic heart failure [55]; the level was also associated with increased risk of death at 1 year for patients with ST-segment-elevated myocardial infarction [56]. Finally, the authors observed the same association at 30 days and 1 year for patients with non-ST-elevated acute coronary syndrome [57]. For all those situations, GDF15 concentration was an independent predictor as compared with other clinical or biological variables. Interestingly, the cutoff level of GDF15 was the median. The same team had also shown that GDF15 was a prognostic factor after acute pulmonary thrombosis [58] and could predict increased risk of death or transplantation for patients with idiopathic pulmonary arterial hypertension [59]. In other clinical situations, such as resynchronization therapy, GDF15 predicted increased mortality and morbidity [60]. However, all these studies concerned relatively older patients, and because GDF15 concentration increases with age, younger patients should be studied. In a study of 317 young adults (mean age, 26.5 years) who had undergone surgery for congenital heart defects more than 10 years previously, GDF15 blood concentration was correlated with other risk factors and could be considered a surrogate marker of heart failure risk even in asymptomatic patients [61].

The biological processes that underlie the relationship between GDF15 and cardiovascular disease are not clear. Indeed, although GDF15 is not produced in healthy cardiomyocytes, its synthesis is induced by various stressors (i.e., oxidative stress, proinflammatory cytokines) in vitro or in the hearts of mice or patients after myocardial infarction [62]. However, this is not the case for nonischemic heart failure. GDF15 is highly produced by macrophages in atherosclerotic lesions, but contradictory results render the interpretation difficult. Johnen et al. found that GDF15 protected apolipoprotein E-deficient mice against atherosclerosis [63] and Bonaterra et al. showed that it inhibited atherosclerosis progression by regulating the IL-6 inflammatory response [64], but de Jager et al. demonstrated that GDF15 deficiency protected against atherosclerosis [34]. Thus, as was shown for cancer, in cardiovascular disease, GDF15 could have opposite effects and certainly depends on the environment. GDF15 protects cardiomyocytes against apoptosis and thus protects the heart in ischemia/reperfusion [65]. However, its role in heart remodeling may be dual: it could have an antihypertrophic effect mediated by the Smad2/3 pathway or a prohypertrophic effect when the Smad1 pathway is activated; furthermore, GDF15 was reported to enhance growth and collagen deposition by cardiac fibroblasts [66].

Other Pathologies

Few additional papers have reported links between elevated plasma concentration of GDF15 and disease states. All these studies were related to chronic diseases, such as rheumatoid arthritis, end-stage renal failure, or diabetes [67–69]. As for cancer or cardiovascular diseases, GDF15 plasma concentration was an independent predictor of disease worsening and/or death. The biological processes that could explain such a link are obscure and often not known. A recent study [70] underlines the positive effects of GDF15 on peripheral nerve regeneration. In this case, GDF15 seems to reduce the number of regenerated axons but it increases the maturation of those that are newly formed. This leads to a better recovery of the sensorimotor function [70].

Conclusion

GDF15 seems to be an integrative signal in pathology. It appears to have both beneficial and adverse effects depending on the state of cells and the microenvironment. However, a reference concentration of GDF15 in plasma needs to be determined according to age and gender for healthy general populations. This reference concentration will facilitate comparative studies.

The perspective of GDF15 is both scientific and clinical. From a scientific point of view, the discovery of the receptor(s) and the downstream signaling pathways is very important to unravel its activity. This will also greatly help its use in the clinic.

In cancer, the GDF15 could be used for prospective studies with large cohorts of patients to determinate the interest in using it as a surrogate prognostic marker in cancers where it has been shown to be elevated in worth cases. Moreover, given the GDF15-induced chemoprotection demonstrated in some cancers, a correlation between GDF15 concentration in serum of patients and their response to treatment should be sought. In the cardiovascular field, GDF15 should be used to stratify the patients and modulate the treatments or the interventions. For example, in young patients who had undergone cure of a congenital heart defect, the surveillance of the GDF15 plasma level may guide pre-emptive treatment for heart failure.

Despite some opposite functions described in tumor process, a clinical perspective for GDF15 in cancer may be to target it. Because of the moderately minor phenotype shown by GDF15-knockout mice, such a strategy might be conceivable [71, 72]. The main brake to its development seems to be the lack of clear knowledge about GDF15 signaling pathways and associated receptors. Hence, the potential adverse effects of anti-GDF15 treatment cannot be anticipated for the moment. However, inhibiting GDF15 is attractive, in particular in tumors where GDF15 involves malignant cells themselves but also tumoral microenvironment; indeed, in myeloma, the microenvironment has such a pivotal role in the pathophysiology of the disease that it became a major therapeutic target. Normalizing specific microenvironment abnormalities in cancer, namely GDF15 overproduction, is a promising therapeutic approach. As thalassemia is a frequent disease causing important morbidity and mortality, targeting GDF15 via its receptor, via specific anti-Smad molecules, or via monoclonal antibody could be of clinical interest for those patients with critical iron overload. Preliminary in vitro laboratory tests have to be performed to first link Smad2/3 to GDF15 in this setting, and an effort will have to be made to identify a receptor for GDF15. In the acute phase after myocardial infarction, GDF15 may be administered to prevent cardiomyocytes hypertrophy. However, it should be used with caution because of the controversial data on its long-term effect on cardiomyocyte hypertrophy.

Author Contributions

J.C.: collection and/or assembly of data, manuscript writing; B.H.: manuscript writing, figure design; P.B.: collection and/or assembly of data, manuscript writing, final approval of manuscript.

Disclosure of Potential Conflicts of Interest

The authors indicate no potential conflicts of interest.

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