TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms

Abstract

The continuing efforts to exploit the death receptor agonists, such as the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), for cancer therapy, have largely been impaired by the anti-apoptotic and pro-survival signalling pathways leading to drug resistance. Cell migration, invasion, differentiation, immune evasion and anoikis resistance are plastic processes sharing features of the epithelial-to-mesenchymal transition (EMT) that have been shown to give cancer cells the ability to escape cell death upon cytotoxic treatments. EMT has recently been suggested to drive a heterogeneous cellular environment that appears favourable for tumour progression. Recent studies have highlighted a link between EMT and cell sensitivity to TRAIL, whereas others have highlighted their effects on the induction of EMT. This review aims to explore the molecular mechanisms by which death signals can elicit an increase in response heterogeneity in the metastasis context, and to evaluate the impact of these processes on cell responses to cancer therapeutics.

Fig. 1. Effects of death receptor agonists on EMT-mediated cancer-cell heterogeneity.

Binding of death ligands can activate pathways, including caspase-8-dependent apoptosis and survival. Cancer cells that survive treatment can give rise to different responses, such as proliferation, senescence or differentiation. Epithelial-to-mesenchymal transition (EMT) is one of the cell biological processes that contributes to cellular plasticity, allowing cancer cells to switch from an epithelial state to a mesenchymal one. Cells lose their adhesion capacities, acquire stem cell characteristics (CSCs) and can migrate until invading secondary sites via the lymphatic system and the blood circulation. EMT also provides resistance to anoikis, an apoptotic process following loss of cell contacts with ECM and decreases the immunogenic response. Together, these events can participate in the increased resistance of circulating tumour cells (CTCs) alone or in clusters (CTMs), allowing cancer progression and metastasis. Finally, EMT increases response heterogeneity by enhancing cell diversity within the tumour, which can further increase clonal heterogeneity and cancer cell resistance to chemotherapies.