Cancer cell cannibalism: Multiple triggers emerge for entosis.

Entosis is a form of epithelial cell engulfment and cannibalism prevalent in human cancer. Until recently, the only known trigger for entosis was loss of attachment to the extracellular matrix, as often occurs in the tumour microenvironment. However, two new studies now reveal that entosis can also occur among adherent epithelial cells, induced by mitosis or glucose starvation. Together, these findings point to the intriguing notion that certain hallmark properties of cancer cells, including anchorage independence, aberrant proliferation and metabolic stress, can converge on the induction of cell cannibalism, a phenomenon so frequently observed in tumours. In this review, we explore the molecular, cellular and biophysical mechanisms underlying entosis and discuss the impact of cell cannibalism on tumour biology.

Entosis: Cell-in-Cell Formation that Kills Through Entotic Cell Death.

Entosis is a cell-in-cell formation mechanism that targets viable cells for uptake in epithelial cell cultures and human tumors. Entotic cells control their own engulfment, by invading into their hosts in a Rho-GTPase and actomyosin-dependent manner. Although entotic cells are internalized while alive, most eventually undergo a non-apoptotic form of cell death, called entotic cell death, that is executed non-cell-autonomously by autophagy proteins and lysosomes. Here we review the current understanding of entosis and entotic cell death and discuss the potential roles of this process in cancer.

Both Fcgamma and complement receptors mediate transfer of immune complexes from erythrocytes to human macrophages under physiological flow conditions in vitro.

Abnormal clearance by the mononuclear phagocytic system of immune complexes (IC) is important in the pathogenesis of systemic lupus erythematosus (SLE). We have developed an in vitro model to investigate the cellular mechanisms involved in the transfer of soluble IC from erythrocytes to human macrophages under physiological flow conditions. In this assay, erythrocytes bearing fluorescently labelled IC are perfused over monolayers of human monocytes or monocyte-derived macrophages in a parallel-plate flow chamber, and transfer quantified using confocal microscopy and flow cytometry. Using aggregated human IgG as a model IC, we have been able to demonstrate transfer of IC from erythrocytes to macrophages. Blocking studies with specific neutralizing antibodies have shown that both complement and Fcgamma receptors are required for IC transfer. Blockade of CR4 (alpha(x)beta(2) integrin), FcgammaRIIa or FcgammaRIII reduced transfer, while anti-CR3 (alpha(m)beta(2) integrin) had no effect. Blockade of CR3, FcgammaRIIa or FcgammaRIII also reduced the number of adhesive interactions between fluorescently labelled IC-bearing erythrocytes and macrophage monolayers. Taken together with the transfer data, this suggests differing roles for these receptors in the human IC transfer reaction that includes an adhesive function which facilitates IC processing by mononuclear phagocytes. Finally, a functional effect of the FcgammaRIIa R131/H131 polymorphism, important in susceptibility to SLE, has also been demonstrated using this model. Uptake of IgG(2) but not IgG(1)-containing soluble IC was reduced by macrophages from individuals homozygous for the R131 allelic variant of the receptor.