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

A cell-in-cell (CIC) structure is formed when one viable cell becomes internalised within

a neighbouring cell. CIC structures have been observed in many human tumours, in

which their occurrence has been associated with high-grade disease or metastasis. On

the contrary, CIC structures have also been suggested to be anti-tumourigenic,

triggering death of matrix-detached cells. The findings presented here show how, in

adherent cancer cell lines, CIC structures form, and that this involves a mechanism of

live cell ‘phagocytic’ engulfment. Interestingly, mutant p53 status affects both the

frequency and subsequent outcomes of these structures. Internalised cells ultimately

either escaped, died, or divided and often appeared to physically interfere in the

cellular divisions of host cells. Host cells were observed to undergo failed and aberrant

division events upon disruption of cytokinesis due to the internalised cell. For cells

without p53, this lead to host cell death. In contrast, mutant p53 host cells survived

aberrant divisions, often becoming multinucleated and undergoing tripolar mitoses. In

tumour xenograft models, mutant p53/null p53 cell co-cultures which had increased

occurrence of CIC structures and also higher final tumour volume on average.

Furthermore, CIC structures were present in 50% of archival human lung cancers in a

cohort of 273 patients. CIC occurrence was an independent predictor of poor outcome,

and was also associated with mutant p53 expression, intra-tumour genomic

heterogeneity and genomic instability. These findings suggest that tumour cell

engulfment activity, in combination with mutant p53 status is pro-tumourigenic in lung

cancers.