Cell cannibalism in cancer
Entosis is a recently discovered process of cell engulfment where live cells get completely internalised by others. In an unusual form of cellular cannibalism, the majority of engulfed cells are killed and digested by their host. The process of entosis is commonly observed in human tumours, constituting a novel mode of tumour suppression. Emerging evidence indicates that entosis is triggered following cell detachment from their underlying extracellular matrix, a phenomenon observed in cancer. However, the precise molecular and cellular mechanisms that drive entosis remain poorly understood. Scientists of the EU-funded ENTOSIS2013 project discovered that cell proliferation in the form of mitosis can also act as a trigger for entosis. Given that aberrant cell proliferation is a hallmark of cancer, these new findings have important clinical implications. To elucidate the mechanism underlying the phenomenon of mitosis-triggered entosis, the consortium depleted specific genes known for their role in epithelial cell biology and extracellular matrix binding, and assessed their impact on entosis. Two components, namely Cdc42 and Rap1, proved necessary for avoiding cell cannibalism through entosis. Monitoring of mitotic entosis in cancer cells grown in vitro in the presence of chemotherapeutic agents demonstrated a positive correlation with cell mitotic index. This indicated that mitosis can drive cell cannibalism in cancer, serving as a potential tumour suppressor. Entosis can also promote outer cell multinucleation, driving aneuploidy and genomic instability in the long term. Interestingly, treatment with chemotherapeutic agents also induced mitotic entosis in cultured cells and mouse xenograft models of breast cancer, unveiling a previously unappreciated new function of these drugs. Taken together, the results of the ENTOSIS2013 project portray a clear correlation between frequency of mitosis and cell cannibalism in human breast cancers. Although the information on mitosis and entosis in cancer as well as chemotherapy warrant further investigation, it illustrates the translational potential of this novel mechanism in diagnosis, prognosis or prediction of therapeutic outcome.
