EMT, CTCs and CSCs in tumor relapse and drug-resistance

Abstract

Tumor relapse and metastasis are the primary causes of poor survival rates in patients with advanced cancer despite successful resection or chemotherapeutic treatment. A primary cause of relapse and metastasis is the persistence of cancer stem cells (CSCs), which are highly resistant to chemotherapy. Although highly efficacious drugs suppressing several subpopulations of CSCs in various tissue-specific cancers are available, recurrence is still common in patients. To find more suitable therapy for relapse, the mechanisms underlying metastasis and drug-resistance associated with relapse-initiating CSCs need to be identified. Recent studies in circulating tumor cells (CTCs) of some cancer patients manifest phenotypes of both CSCs and epithelial-mesenchymal transition (EMT). These patients are unresponsive to standard chemotherapies and have low progression free survival, suggesting that EMT-positive CTCs are related to co-occur with or transform into relapse-initiating CSCs. Furthermore, EMT programming in cancer cells enables in the remodeling of extracellular matrix to break the dormancy of relapse-initiating CSCs. In this review, we extensively discuss the association of the EMT program with CTCs and CSCs to characterize a subpopulation of patients prone to relapses. Identifying the mechanisms by which EMT-transformed CTCs and CSCs initiate relapse could facilitate the development of new or enhanced personalized therapeutic regimens.

Keywords: CSCs; CTCs; EMT; clinical trials; tumor relapse.

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.

Figure 2. Understanding the dynamic equilibrium between EMT positive CTCs and CSCs to define tumor relapse

Periodic chemo- or radiotherapy on primary tumor induces EMT positive tumor cells. These EMT positive tumor cells are transformed into quiescent CTCs upon entering into the bloodstream. These EMT positive CTCs express Plastin 3 (PLS3) and cell surface Vimentin (CSV) on its surface. During relapse phase, EMT positive CTCs reprogram into drug-resistant EMT positive CSCs under ambient condition to cause poor survival rate for cancer patients.