Untitled ItemThe biology of mutant p53 associated cell-in-cell formation in cancer.

<div>A cell-in-cell (CIC) structure is formed when one viable cell becomes internalised within</div><div>a neighbouring cell. CIC structures have been observed in many human tumours, in</div><div>which their occurrence has been associated with high-grade disease or metastasis. On</div><div>the contrary, CIC structures have also been suggested to be anti-tumourigenic,</div><div>triggering death of matrix-detached cells. The findings presented here show how, in</div><div>adherent cancer cell lines, CIC structures form, and that this involves a mechanism of</div><div>live cell ‘phagocytic’ engulfment. Interestingly, mutant p53 status affects both the</div><div>frequency and subsequent outcomes of these structures. Internalised cells ultimately</div><div>either escaped, died, or divided and often appeared to physically interfere in the</div><div>cellular divisions of host cells. Host cells were observed to undergo failed and aberrant</div><div>division events upon disruption of cytokinesis due to the internalised cell. For cells</div><div>without p53, this lead to host cell death. In contrast, mutant p53 host cells survived</div><div>aberrant divisions, often becoming multinucleated and undergoing tripolar mitoses. In</div><div>tumour xenograft models, mutant p53/null p53 cell co-cultures which had increased</div><div>occurrence of CIC structures and also higher final tumour volume on average.</div><div>Furthermore, CIC structures were present in 50% of archival human lung cancers in a</div><div>cohort of 273 patients. CIC occurrence was an independent predictor of poor outcome,</div><div>and was also associated with mutant p53 expression, intra-tumour genomic</div><div>heterogeneity and genomic instability. These findings suggest that tumour cell</div><div>engulfment activity, in combination with mutant p53 status is pro-tumourigenic in lung</div><div>cancers.</div>