Figure 1. Tumor relapse driven by EMT-positive CTCs and CSCs.
Upon anti-cancer therapy of primary tumors, EMT-positive CTCs are detected in large numbers in the peripheral blood. These CTCs migrate through organs such as the liver, lungs, lymph nodes, and bone marrow. Once the tumor cells arrive at their site of relapse, they remain dormant for an extended period and transform into CSCs. ECM remodeling; p38α, NR2F1, and TGFβ2 signaling; and inhibition of ERK1/2, FAK, FOXM1, and c-JUN pathways facilitate dormancy. Furthermore, tumor-associated tissue environments provide an embedded niche to protect these cells from anti-cancer therapies or any other lethal damage. Under ambient conditions, with ECM remodeling and activation of proliferative, angiogenic signaling pathways, EMT-positive CSCs undergo proliferation to initiate recurrence. These cells are highly resistant to anti-cancer drugs and are capable of evading immune surveillance.