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.
Highlights
The advancement of molecular and cell biology in the last century often makes us believe that most, if not all, phenomena which can be observed in light microscopy have already been discovered and described.there exist many unresolved issues in this field, as has been demonstrated by the rediscovery of the process of enclosure of one eukaryotic cell inside another, which is collectively called internalization
Cancerous cells tend to form homotypic CIC structures and their presence suppresses metastases. These CIC structures morphologically resemble entosis, they are a result of homotypic cell cannibalism (HoCC), which has only been reported in the literature once [43]
Despite the fact that CIC formation still remains poorly understood, preliminary studies suggest the involvement of different processes, collectively described under this umbrella term, in various physiological and pathological mechanisms such as tumor progression, tissue homeostasis, immune response modulation, inflammation, neurodegeneration, platelet membrane circulation, Rosai–Dorfman disease, and many others [30,33,47,70,76,87]
Summary
The advancement of molecular and cell biology in the last century often makes us believe that most, if not all, phenomena which can be observed in light microscopy have already been discovered and described. Emperipolesis is a process involving heterotypic CICs, in which the inner cell is usually a leukocyte. Entosis is an invasive homotypic CIC state, which always involves two or more epithelial and usually cancerous cells. During this process, the inner cell can either survive or die via the lysosomal pathway [7,11]. Cancerous cells tend to form homotypic CIC structures and their presence suppresses metastases These CIC structures morphologically resemble entosis, they are a result of homotypic cell cannibalism (HoCC), which has only been reported in the literature once [43]. The molecular regulation and triggering factors of the process have not been elucidated
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