Editors' ChoiceCell death

Die Another Way

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Science's STKE  04 Dec 2007:
Vol. 2007, Issue 415, pp. tw443
DOI: 10.1126/stke.4152007tw443

Epithelial cells depend for their survival on integrin-mediated signals generated by attachment to the extracellular matrix (ECM). Epithelial cells also form adherens junctions that are dependent on interactions between cadherin proteins on adjacent cells. Detachment of epithelial cells from the ECM triggers their apoptotic cell death in a process known as anoikis. Overholtzer et al. were studying small aggregates of human mammary epithelial cells (MCF10A) in suspension when they noticed that some cells were contained within large vacuoles in other cells. By labeling populations of cells with different fluorescent dyes and mixing the cells, the authors found that cell invasion occurred within a few hours of detachment from the ECM. Whereas cell invasion was not prevented by inhibitors of apoptosis, its occurrence was reduced by inhibitors of actin polymerization or myosin contraction. Inhibition of the guanosine triphosphatase Rho, which regulates actin and myosin, or of its downstream target Rho-associated kinase (ROCK) prevented epithelial cell internalization. Further experiments with differentially labeled and differentially treated cells showed that Rho and ROCK activity in the invading cells were necessary for cell invasion, which the authors refer to as entosis. An antibody against E-cadherin inhibited both the formation of MCF10A aggregates and entosis. Fluorescent microscopy showed that, whereas the invading cells did not contain activated caspase-3, a marker of apoptosis, many of the invading cells colocalized with host cell lysosomal markers and the protease cathepsin B. Finally, immunohistochemical analyses showed evidence of entosis in human primary and metastatic breast tumors. As White points out in commentary, entosis may be a mechanism by which epithelial cancers, characterized by unregulated proliferation of detached epithelial cells, may be suppressed.

M. Overholtzer, A. A. Mailleux, G. Mouneimne, G. Normand, S. J. Schnitt, R. W. King, E. S. Cibas, J. S. Brugge, A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966-979 (2007). [PubMed]

E. White, Entosis: It’s a cell-eat-cell world. Cell 131, 840-842 (2007). [PubMed]

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