The role of autophagy in the cross-talk between epithelial-mesenchymal transitioned tumor cells and cancer stem-like cells

Abstract

Epithelial-mesenchymal transition (EMT) and cancer stem-like cells (CSC) are becoming highly relevant targets in anticancer drug discovery. A large body of evidence suggests that epithelial-mesenchymal transitioned tumor cells (EMT tumor cells) and CSCs have similar functions. There is also an overlap regarding the stimuli that can induce the generation of EMT tumor cells and CSCs. Moreover, direct evidence has been brought that EMT can give rise to CSCs. It is unclear however, whether EMT tumor cells should be considered CSCs or if they have to undergo further changes. In this article we summarize available evidence suggesting that, indeed, additional programs must be engaged and we propose that macroautophagy (hereafter, autophagy) represents a key trait distinguishing CSCs from EMT tumor cells. Thus, CSCs have often been reported to be in an autophagic state and blockade of autophagy inhibits CSCs. On the other hand, there is ample evidence showing that EMT and autophagy are distinct events. CSCs, however, represent, by themselves, a heterogeneous population. Thus, CSCs have been distinguished in predominantly non-cycling and cycling CSCs, the latter representing CSCs that self-renew and replenish the pool of differentiated tumor cells. We now suggest that the non-cycling CSC subpopulation is in an autophagic state. We propose also two models to explain the relationship between EMT tumor cells and these two major CSC subpopulations: a branching model in which EMT tumor cells can give rise to cycling or non-cycling CSCs, respectively, and a hierarchical model in which EMT tumor cells are first induced to become autophagic CSCs and, subsequently, cycling CSCs. Finally, we address the therapeutic consequences of these insights.

Autophagy in stem cells: repair, remodelling and metabolic reprogramming

“…The role of autophagy in the survival of CSCs and the maintenance of stemness has also been described in other tumour types (Auberger and Puissant, 2017;Hamaï et al, 2014;Lin et al, 2015;Marcucci et al, 2017;Ojha et al, 2015). However, the role of autophagy in CSCs is probably more complex, as demonstrated by the fact that autophagy inhibition decreases the viability of chronic myeloid leukaemia CD34 + progenitor cells, whereas its inhibition in HSCs favours the expansion of acute myeloid leukaemia progenitor cells (Auberger and Puissant, 2017).…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…185 Through autophagy, cancer cells and especially cancer stem-like cell clones increase their capacity for material turnover and efflux of cancer drugs. 192 Moreover, CSC markers and autophagy have been associated with poor prognosis in pancreatic cancer patients. 188 These protective effects of autophagy on CSC have been consistently shown in various cancers including colon and breast cancers and chronic myeloid leukemia.…”

“…[189][190][191] In addition, autophagy was proposed to enable neoplastic cells that have undergone epithelial-to-mesenchymal transitions to acquire CSC traits. 192 Moreover, CSC markers and autophagy have been associated with poor prognosis in pancreatic cancer patients. 193 Therefore, inhibition of autophagy is a promising approach to overcome chemotherapy resistance and consequently to eradicate tumor cells by reducing tumor heterogeneity.…”

Targeting autophagy in thyroid cancers

“…Epithelial-to-mesenchymal transition (EMT) is associated with the development and invasion of thyroid cancers, especially PTC and ATC (Hardy et al 2007, Hardin et al 2017. EMT and autophagy are two distinct events but a cross-talk exists between these two events in a controversial way (Marcucci et al 2017).…”