Study of cell-in-cell phenomena began with the desire to understand the complex phenotype, which stemmed from Lewis' observation of non-phagocytotic process of cell-eating-cell in 1925 1. Humble et al. coined the term “emperipolesis” (from the Greek, wandering round about within) in 1950s, to define the heterogeneous cell-in-cell phenomena when they studied biological interaction of lymphocytes with other cells 2. Emperipolesis has since been found to be commonly enacted by lymphocytes in physiological and pathophysiological settings 3. Since the term “emperipolesis” was annotated, a challenge has been set to understand how a cell inhabits in the other, what are their respective fates, and the biological relevance of co-habitation. Recently, Overholtzer et al. observed a homogeneous cell-in-cell phenomenon and named it as “entosis” (from the Greek, inside), an intercellular process that exhibits remarkable similarity to emperipolesis 4. Further investigation of this entotic process revealed that it requires the formation of adherens junctions in the absence of integrin signaling, and force-driven invasion of one cell into another cell. In addition, the process requires the Rho-ROCK signaling pathway of the invading cell and myosin-based contractile force from the recipient cell. Surprisingly, some invading cells chose to run away via a transcytosis-like movement while a small percentage of invading cells underwent cell division within the host cells.

Cell-cell adhesion is critical for the plasticity in tissues and organs. Adherens junctions are intercellular structures prominent in epithelia and neurons, which is composed of cadherins. Both emperipolesis and entosis require extracellular free calcium and adhesion molecules and actin-based cytoskeleton. Vasioukhin et al. reported that epithelial cells engage in a process of cadherin-mediated intercellular adhesion that utilizes calcium and involves actin polymerization 7, reminiscent of the initial phase of entotic and emperipoletic processes. Although it has long been recognized that calcium stimulates homotypic engagement of cadherins essential for intercellular adhesion 8, the precise mechanism for the calcium requirement is unclear. It seems likely that calcium and perhaps other divalent cations such as magnesium activate some key regulatory molecule(s) that in turn leads to actin polymerization at filopodia growth sites. Given the remodeling of cytoskeleton underlying the aforementioned processes, it would be of great interest to monitor whether intracellular calcium is mobilized and how. To systematically delineate emperipolesis and entosis, it would also be necessary to identify the key intercellular connection molecules essential for the initial target survey and conjugation. Molecular characterization of protein-protein interactions underlying the aforementioned conjugation will be essential for illustrating the spatiotemporal dynamics of emperipolesis and entosis.

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