Cell Death by Entosis: Triggers, Molecular Mechanisms and Clinical Significance

Abstract

Entosis—a homotypic insertion of one cell into another, resulting in a death of the invading cell—has been described in many reports, but crucial aspects of its molecular mechanisms and clinical significance still remain controversial. While actomyosin contractility of the invading cell is very well established as a driving force in the initial phase, and autophagy induced in the outer cell is determined as the main mechanism of degradation of the inner cell, many details remain unresolved. The multitude of triggering factors and crisscrossing molecular pathways described in entosis regulation make interpretations difficult. The question of the physiological role of entosis also remains unanswered. In this review, we summarize the knowledge of molecular mechanisms and clinical data concerning entosis accumulated so far, highlighting both coherent explanations and controversies.

The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

“…8 A and B). RHOA/ROCK-controlled pathways and actomyosin contractility of the invading cell are the known driving force for the initiation of entosis 45 , 46 , which is in agreement with our observation that entosis of HGSC cells is dependent on both MYPT1 and ROCK (Fig. 9 A and B).…”

“…9 A). Even though the association of entosis with progression of HGSC remains to be investigated, entosis may contribute to cancer cell survival under stress conditions (such as chemotherapy) 45 , 46 as well as to their escape from immune surveillance 132 . Furthermore, MYPT1 phosphorylation is induced by LPA in both OCMI91s and OVCAR8 cells with different LPAR expression profile ( Fig.…”

“…Entosis provides a potential survival advantage for the outer cell under unfavorable conditions, such as starvation or exposure to anti-cancer drugs [44][45][46]. Intriguingly, entosis appears to have prognostic value in a majority of cancers, including head and neck, lung, pancreatic and breast carcinomas, where the frequency of entotic figures is associated with malignancy and a poor prognosis [45].…”

“…LPA also contributes to drug resistance by maintaining OC stem cells [39] and interfering with the type I interferon response [40]. LPA has further been shown to trigger cell-in-cell invasion (entosis) in tumor cells [41], which may, in an entity-dependent manner, have either pro-tumorigenic or anti-tumorigenic effects in different entities [42][43][44][45][46]. In HGSC specifically, a role for entosis has yet to be explored.…”

To Die or Not to Die: Cell Death in Biology and Disease

“…In 2007, Overholtzer et al [ 7 ] reported that detached epithelial cells can also take an alternative route to death called entosis, which is driven by cell-in-cell invasion ( Figure 1 C). For this Special Issue, Kianfar et al [ 8 ] summarized the current knowledge of molecular mechanisms and clinical data on entosis, highlighting both conclusive explanations and controversies.…”