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A cell-in-cell (CIC) structure is formed when one viable cell becomes internalised withina neighbouring cell. CIC structures have been observed in many human tumours, inwhich their occurrence has been associated with high-grade disease or metastasis. Onthe contrary, CIC structures have also been suggested to be anti-tumourigenic,triggering death of matrix-detached cells. The findings presented here show how, inadherent cancer cell lines, CIC structures form, and that this involves a mechanism oflive cell ‘phagocytic’ engulfment. Interestingly, mutant p53 status affects both thefrequency and subsequent outcomes of these structures. Internalised cells ultimatelyeither escaped, died, or divided and often appeared to physically interfere in thecellular divisions of host cells. Host cells were observed to undergo failed and aberrantdivision events upon disruption of cytokinesis due to the internalised cell. For cellswithout p53, this lead to host cell death. In contrast, mutant p53 host cells survivedaberrant divisions, often becoming multinucleated and undergoing tripolar mitoses. Intumour xenograft models, mutant p53/null p53 cell co-cultures which had increasedoccurrence of CIC structures and also higher final tumour volume on average.Furthermore, CIC structures were present in 50% of archival human lung cancers in acohort of 273 patients. CIC occurrence was an independent predictor of poor outcome,and was also associated with mutant p53 expression, intra-tumour genomicheterogeneity and genomic instability. These findings suggest that tumour cellengulfment activity, in combination with mutant p53 status is pro-tumourigenic in lungcancers. |
