OPINION

Cell-in-cell phenomena in cancer

Abstract

Cell-in-cell structures are reported in numerous cancers, and their presence is an indicator for poor prognosis. Mechanistic studies have identified how cancer cells manage to ingest whole neighbouring cells to form such structures, and the consequences of cell-in-cell formation on cancer progression have been elucidated. In this Opinion article, we discuss how two related cell-in-cell processes, cell cannibalism and entosis, are regulated and how these mechanisms promote cancer progression. We propose that cannibalistic activity is a hallmark of cancer that results in part from selection by metabolic stress and serves to feed aggressive cancer cells.

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Fig. 1: Regulation of cannibalism and entosis.
Fig. 2: Consequences of cannibalism and entosis.

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Acknowledgements

This work was supported by grants from the Ministry of Health, Italy (S.F.) and the US National Institutes of Health (CA154649; M.O.). The authors included many different examples of published reports of cell-in-cell activity in cancer in Box 1 of this review to show the breadth of this activity; the authors apologize to those whose work was not included owing to space limitations.

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Nature Reviews Cancer thanks E. Moreno, M. Olson and A. Thorburn for their contribution to the peer review of this work.

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Both authors contributed equally to this work.

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Correspondence to Stefano Fais or Michael Overholtzer.

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Glossary

Cannibalism

The engulfment of live or dead cells or debris by cancer cells as described in metastatic melanoma; also used frequently as a general term for engulfment.

Cell-in-cell

A general term used to describe the appearance of whole, typically live, cells ingested into other cells.

Emperipolesis

A general term that describes the uptake of live cells and their movement inside host cells. Suicidal emperipolesis is the mechanism of invasion of live T cells into hepatocytes.

Emperitosis

A mechanism resembling entosis and involving natural killer cells that invade into cancer cells and die by granzyme B-mediated cell death.

Entosis

The uptake of live cells into other cells through an invasive mechanism; entosis typically involves cell–cell adhesion proteins and actomyosin-mediated contraction within invading cells regulated by RHO GTPases and RHO-associated coiled-coil-containing protein kinase (ROCK).

Homotypic cell cannibalism

A term describing a homotypic engulfment mechanism suggested to involve pancreatic cancer cells.

Phagocytosis

The engulfment of dying or dead cells or microorganisms through receptor-mediated mechanisms.

Phagoptosis

The uptake and killing of live cells through phagocytosis.

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Fais, S., Overholtzer, M. Cell-in-cell phenomena in cancer. Nat Rev Cancer 18, 758–766 (2018). https://doi.org/10.1038/s41568-018-0073-9

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