A Nonapoptotic Cell Death Process, Entosis, that Occurs by Cell-in-Cell Invasion

Abstract

Epithelial cells require attachment to extracellular matrix (ECM) to suppress an apoptotic cell death program termed anoikis. Here we describe a nonapoptotic cell death program in matrix-detached cells that is initiated by a previously unrecognized and unusual process involving the invasion of one cell into another, leading to a transient state in which a live cell is contained within a neighboring host cell. Live internalized cells are either degraded by lysosomal enzymes or released. We term this cell internalization process entosis and present evidence for entosis as a mechanism underlying the commonly observed "cell-in-cell" cytological feature in human cancers. Further we propose that entosis is driven by compaction force associated with adherens junction formation in the absence of integrin engagement and may represent an intrinsic tumor suppression mechanism for cells that are detached from ECM.

Entosis, a key player in cancer cell competition

“…Inhibition of RhoA by overexpression of RhoA-N19 or p190A RhoGAP was sufficient to impart winner status to cells mixed with controls, whereas overexpression of RhoA, ROCKI, or ROCKII had the opposite effect and hence created 'loser' cells [5]. It has been known that RhoGTPase and Rho-kinase are not required in engulfing cells but are required in internalizing cells [1], underscoring the idea that 'loser' cells are not just passive 'victims' of a cannibalistic attack but somehow contribute to their fatal fate. The 'loser' status was accompanied by the ROCK-dependent accumulation of actomyosin [6], and computer simulations suggest that actomyosin contractility within 'loser' cells constitutes a critical driving force of entosis [5].…”

“…Importantly, co-culture of non-transformed cells with their malignant counterparts systematically leads to engulfment of the former by the latter, suggesting that oncogenic transformation is coupled to the 'winner' status [5]. Indeed, competition by entosis leads to the physical elimination of the 'loser' cells, which usually succumb to non-apoptotic cell death as soon as the phagosome enveloping the engulfed cell is decorated with LC3 and then fuses with lysosomes [1,7]. What is then the difference between 'loser' and 'winner' cells?…”

L’entose, mort cellulaire par cannibalisme entre cellules tumorales

“…Récemment, un autre processus de mort cellulaire alternatif a été mis en évi-dence lorsque des cellules épithéliales perdent contact avec leur substrat in vitro [6]. Ainsi, des cellules de lignées épithéliales d'origine mammaire peuvent aussi former en suspension des agrégats où des cellules se retrouvent complètement encapsulées dans des vacuoles au sein de cellules voisines (Figure 1).…”

“…Ainsi, des cellules de lignées épithéliales d'origine mammaire peuvent aussi former en suspension des agrégats où des cellules se retrouvent complètement encapsulées dans des vacuoles au sein de cellules voisines (Figure 1). Ce processus nommé « entose », du grec entos (« dedans ») se déroulait en parallèle de l'anoikis dans ce modèle in vitro [6]. À première vue, la concomitance de ces deux processus pourrait suggérer que ce phé-nomène d'internalisation correspond à la phagocytose de cellules mortes en anoikis par leurs voisines encore en vie.…”

“…Enfin, des études récentes menées chez la souris ont soulevé l'hypothèse mésenchymateuse. L'équipe de Suzan Backer a ainsi pu mettre en évidence que l'expression d'EWS-FLI-1 dans des cellules stromales osseuses bloquait leur différenciation terminale dans les voies adipocytaire et ostéocytaire [6]. Puis les équipes de Robert Ilaria et d'Ivan Stamenkovic ont montré que des cellules stromales osseuses exprimant EWS-…”