(Image: Nature Reviews, Molecular Cell Biology, Sep 2008, DOI 10.1038/nrm2504)
Cell death is not always a road to perdition. Yes, cells need to survive to carry out the physiological functions essential to maintain life and most animal cells survive by attachment to an extracellular matrix (ECM). Yet, the loss of ECM-detached epithelial cells proves beneficial and essential for lumen formation during mammary gland development and to prevent breast tumor formation. Death of ECM-deprived cells occurs primarily via an apoptotic mechanism called anoikis. Recent studies, however, reveal that blocking anoikis is insufficient to prevent the long-term loss of detached tumor cells, suggesting the presence of non-apoptotic, detachment-induced cell death mechanisms. In Nov. 2007 issue of the journal “Cell”, the Overholtzer group from Harvard Medical School reported a hitherto unknown mechanism of cell death called “Entosis” and provided evidence for its potential role in “cell-in-cell” process observed in human cancers. “Entosis” or “cell-eating-cell” or “cell-in-cell” occurs by the invasion of detached cells into vacuoles within neighboring cells. Observing healthy human breast cells in suspension cultures, the group discovered that internalizing cells actively participate in the invasion process, which depends on Rho-GTPase mediated signaling to generate contractile force for invasion. Before internalization, the participating cells attach to each other by forming cadherin-mediated adherens junctions. The entosed cells remain viable for 48 h and while majority of these cells eventually die by lysosomal degradation, some can divide actively and even released unharmed. The study showed that inhibition of other cell death pathways—apoptosis and phagocytosis—did not impede the progression of entosis, providing further evidence of the observation of novel biological process. To test if entosis observed in healthy cells in vitro is physiologically relevant and if it actually occurs in tumor cells, the authors collected pleural fluid and solid tumor samples from patients and showed that both classes of tumors do show the characteristics of entosis: formation of cadherin-mediated cell-cell junction and presence of cells in lysosomal compartments.
Being a novel phenomenon, entosis has brought with it more questions than it has answered in Overholtzer’s study. So far entosis has been observed only in vitro, its significance or even existence in vivo remains unanswered. Since entosed cells may replicate and even escape cell death, critics argue that tumor cells may exploit entosis to avoid recognition by chemotherapeutic drugs or by body immune system by hiding out inside another cell. The survival of some entosed cells also fuels the argument that entosis might not be effective in suppressing tumor progression and that this process occurs only in vitro but not in a living body. We have to wait for more of entosis to know whether it is a fluke observed in cultured cells or a genuine performer of tumor suppression. Given the fact that tumor cells in culture undergo entosis and that majority of entosed cells succumb to death, this phenomenon of cell cannibalism is very likely to inhibit tumor progression by killing cancer cells. Sure enough, cell death is not always a road to perdition.
For video on entosis: http://www.youtube.com/watch?v=Zp61OzvKRHYReference: Cell, Volume 131, Issue 5, 966-979, 30 November 2007, or http://www.cell.com/abstract/S0092-8674(07)01394-3
Further reading: Nature Reviews Molecular Cell Biology aOP, published online 11 Sep 2008; doi:10.1038/nrm2504
