Cell-in-Cell Phenomenon and Its Relationship With Tumor Microenvironment and Tumor Progression: A Review

Abstract

The term cell-in-cell, morphologically, refers to the presence of one cell within another. This phenomenon can occur in tumors but also among non-tumor cells. The cell-in-cell phenomenon was first observed 100 years ago, and it has since been found in a variety of tumor types. Recently, increasing attention has been paid to this phenomenon and the underlying mechanism has gradually been elucidated. There are three main related process: cannibalism, emperipolesis, and entosis. These processes are affected by many factors, including the tumor microenvironment, mitosis, and genetic factors. There is considerable evidence to suggest that the cell-in-cell phenomenon is associated with the prognosis of cancers, and it promotes tumor progression in most situations. Notably, in pancreatic cancer, the cell-in-cell phenomenon is associated with reduced metastasis, which is the opposite of what happens in other tumor types. Thus, it can also inhibit tumor progression. Studies show that cell-in-cell structure formation is affected by the tumor microenvironment, and that it may lead to changes in cellular characteristics. In this review, we summarize the different cell-in-cell processes and discuss their role in tumor progression and how they are regulated by different mechanisms.

Multiple cell death modalities and their key features (Review)

“…Paradoxically, impeded autophagy is also associated with tumorigenesis (69). Fourthly, entosis represents tumor suppressive activity in pancreatic cancer, whereas it promotes tumor progression in most other situations (70,71). Although the other cell death types are much less endogenously involved in cancer development, they are mostly utilized as anti-cancer defense strategies of the body and defects in their signaling plays an important role in drug resistance and clinical failures.…”

Entosis: From Cell Biology to Clinical Cancer Pathology

“…There was only one case in which CIC structures were associated with reduced metastasis in pancreatic cancer, which is the opposite to other tumour types [ 25 , 26 ]. However, one should keep in mind that the fate of entosis can be affected by the interactions of cancer cell and tumour extracellular matrix [ 27 ]. As the majority of cancers entosis correlates with poor outcome recurrence of disease [ 1 , 27 ], it can also be hypothesized that the inner entotic cell can survive unfavourable conditions caused by anticancer drugs within the host outer cell, protected by the environment of the entotic vacuole.…”

“…However, one should keep in mind that the fate of entosis can be affected by the interactions of cancer cell and tumour extracellular matrix [ 27 ]. As the majority of cancers entosis correlates with poor outcome recurrence of disease [ 1 , 27 ], it can also be hypothesized that the inner entotic cell can survive unfavourable conditions caused by anticancer drugs within the host outer cell, protected by the environment of the entotic vacuole. Subsequently, the internal cell can leave the outer cell after a long time [ 2 ].…”

Identification and validation of heterotypic cell-in-cell structure as an adverse prognostic predictor for young patients of resectable pancreatic ductal adenocarcinoma

“…Therefore, CICs are ideal candidates for the functional readout of malignant progression. CICs have been identified in several types of cancers 24 , and have been suggested to be related to either tumor suppression 25 or progression 26, 27 . However, due to the lack of systematic analyses associating the presence of distinct types of CICs with patient clinicopathological history, their impact on patients’ prognosis remains to be elucidated.…”