Cancer cell cannibalism is currently defined as a phenomenon in which an
ensemble of a larger cell containing a smaller one, often in a big cytoplasmic vacuole, is
detected in either cultured tumor cells or a tumor sample. After almost one century of
considering this phenomenon as a sort of neglected curiosity, some recent studies have first
proposed tumor cell cannibalism as a sort of “aberrant phagocytosis”, making malignant cells
very similar to professional phagocytes. Later, further research has shown that, differently to
macrophages, exclusively ingesting exogenous material, apoptotic bodies, or cell debris,
tumor cells are able to engulf other cells, including lymphocytes and erythrocytes, either dead or alive, with the
main purpose to feed on them. This phenomenon has been associated to the malignancy of tumors, mostly
exclusive of metastatic cells, and often associated to poor prognosis. The cannibalistic behavior increased
depending on the microenvironmental condition of tumor cells, such as low nutrient supply or low pH,
suggesting its key survival option for malignant cancers. However, the evidence that malignant cells may
cannibalize tumor-infiltrating lymphocytes that act as their killers, suggests that tumor cell cannibalism could be
a very direct and efficient way to neutralize immune response, as well.
Tumor cell cannibalism may represent a sign of regression to a simpler, ancestral or primeval life style, similar
to that of unicellular microorganisms, such as amoebas, where the goal is to survive and propagate in an
overcrowded and very hostile microenvironment. In fact, we discovered that metastatic melanoma cells share
with amoebas a transmembrane protein TM9SF4, indeed related to the cannibal behavior of these cells.
This review attempts to provide a comprehensive description of the current knowledge about the role of
TM9SF4 in cancer, highlighting its role as a key player in the cannibal behavior of malignant cancer cells.
Moreover, we discuss differences and similarities between tumor cannibalism, entosis, phagocytosis and