Classification of Cell-in-Cell Structures: Different Phenomena with Similar Appearance

Abstract

A phenomenon known for over 100 years named “cell-in-cell” (CIC) is now undergoing its renaissance, mostly due to modern cell visualization techniques. It is no longer an esoteric process studied by a few cell biologists, as there is increasing evidence that CICs may have prognostic and diagnostic value for cancer patients. There are many unresolved questions stemming from the difficulties in studying CICs and the limitations of current molecular techniques. CIC formation involves a dynamic interaction between an outer or engulfing cell and an inner or engulfed cell, which can be of the same (homotypic) or different kind (heterotypic). Either one of those cells appears to be able to initiate this process, which involves signaling through cell–cell adhesion, followed by cytoskeleton activation, leading to the deformation of the cellular membrane and movements of both cells that subsequently result in CICs. This review focuses on the distinction of five known forms of CIC (cell cannibalism, phagoptosis, enclysis, entosis, and emperipolesis), their unique features, characteristics, and underlying molecular mechanisms.

Cell-in-Cell Events in Oral Squamous Cell Carcinoma

“…A CIC structure is morphologically identified as the presence of one or more living cells encapsulated within another, residing inside a vacuole that pushes the outer cell's spindle-shaped nucleus towards its periphery (5,6) (Figure 1). This feature was first reported over a century ago (7)(8)(9), when little was known about its composition, mechanism of biogenesis or the implications of its existence.…”

“…Overholtzer (5), on the other hand, proposed that emperipolesis should be defined as a generic term which describes all cell movements associated with CIC structures, regardless of their formation mechanisms (cannibalism or entosis). Borensztejn et al (6) classifies emperipolesis as CIC formation through heterotypic cell invasion, usually by a lymphocyte.…”

“…Recently, Borensztejn et al. ( 6 ) proposed a classification system for CIC structures based on their initiation mechanism. CIC structures are either formed through endocytosis-like steps, as is the case with cell cannibalism, phagoptosis and enclysis); or through inner-cell invasion, in entosis and emperipolesis.…”

“…Through entosis, cells can survive in such harsh conditions. Similarly, other harmful events may favor entosis, such as ultraviolet radiation ( 80 ) and chemotherapy ( 6 ).…”

“…The role of entosis in tumor progression and suppression is more complex than cell cannibalism ( 6 ). On one hand, it may favor cell survival of starving cells ( 68 ) and occur because of chemotherapeutic or other harmful agents ( 6 ). Entosis may also promote aneuploidy and accumulation of cell mutations ( 40 ).…”