By what mechanisms do cell-in-cell

By what mechanisms do cell-in-cell structures form? We have reviewed here two of the best-characterized mechanisms underlying cell-in-cell activity in cancers: cannibalism and entosis. While these mechanisms clearly differ, more remains to be learned about how these are executed. Do cannibalism and entosis share mechanistic similarities? Recently, a homotypic mechanism of cannibalism was reported in pancreatic cancers called homotypic cell cannibalism. While this process, like entosis, targeted cells for homotypic ingestion, it appeared to differ from the entosis mechanism and did not involve ROCK activity8. On the other hand, cannibalistic activity by MDA-MB-231 breast cancer cells directed towards MSCs, a heterotypic form of cell ingestion, was argued not to occur by entosis and yet intriguingly required ROCK16, suggesting mechanistic parallels. Another heterotypic mechanism that drives natural killer cell uptake into tumour cells has been shown, intriguingly, to require E-cadherin and ezrin, which is known to regulate entosis as well as cell cannibalism7,32,59,60. Finally, MDA-MB-468 breast cancer cells, which are deficient for entosis owing to loss of expression of the cell adhesion protein α-catenin61, have been shown to ingest their neighbours at high rates when overexpressing the LIP isoform of the C/EBPβ transcription factor, and this process also required ROCK activity62. How these different cell ingestion mechanisms may resemble or differ from each other remains to be explored in further studies, for example, by probing the requirement of cell adhesion proteins, ROCK, ezrin or caveolin for cell uptake or by examining potentially active roles of the internalizing cells in driving cell-in-cell formation. How cannibalistic mechanisms relate to phagocytosis also remains an important, open question. For all cellin-cell processes, continued elucidation of molecular machinery will be essential to further define the roles of these processes in cancer, particularly for further examination of the roles of these processes in vivo. The presence of entosis, for example6,30, and its consequences on cell populations6,47 are typically defined by dependence on RHOA, ROCK and cadherins, but loss of function for these regulators can have pleiotropic effects. The identification of additional machinery controlling cell-in-cell processes will be important in further studies.