Entosis: The emerging face of non-cell-autonomous type IV programmed death

Martins, Isabelle; Raza, Syed Qasim; Voisin, Laurent; Dakhli, Haithem; Law, Frédéric; Jong, Dorine de; Allouch, Awatef; Thoreau, Maxime; Brenner, Catherine; Deutsch, Éric; Perfettini, Jean-Luc

doi:10.1016/j.bj.2017.05.001

Cited by 45 publications

(41 citation statements)

References 76 publications

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“…It’s now clear that cell death programs, such as apoptosis, necroptosis and autosis, were genetically controlled ( 12 ). As a non-autonomous cell death mechanism that involves at least two cells ( 13 ), CIC-mediated death was conceivably subjected to more complex regulation. Though due to technical limitations, a systemic screening for CIC-associated genes remains to be made.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation

Ruan

Wang

Chen³

et al. 2018

BMB Rep.

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Homotypic cell-in-cell (CIC) structures forming between cancer cells were proposed to promote tumor evolution via entosis, a nonapoptotic cell death process. However, the mechanisms underlying their formation remained poorly understood. We performed a microarray analysis to identify genes associated with homotypic CIC formation. Cancer cells differing in their ability to form homotypic CIC structures were selected for the study. Association analysis identified 73 probe sets for 62 candidate genes potentially involved in CIC formation. Among them, twenty-one genes were downregulated while 41 genes were upregulated. Pathway analysis identified a gene interaction network centered on IL-8, which was upregulated in high CIC cells. Remarkably, CIC formation was significantly inhibited by IL-8 knockdown and enhanced upon recombinant IL-8 treatment, which correlated with altered cell-cell adhesion and expression of adhesive molecules such as P-cadherin and γ-catenin. Together, our work identified IL-8 as a positive regulator of homotypic CIC formation via enhancing intercellular adhesion.

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Section: Discussionmentioning

confidence: 99%

Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation

Ruan

Wang

Chen³

et al. 2018

BMB Rep.

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“…Multiple mechanisms, such as entosis, emperitosis, and homotypical cell cannibalism, have been proposed to promote CIC formation either homotypically between tumor cells or heterotypically between lymphocytes and tumor cells, which generally leads to the death of the internalized cells (5,6). The death of the engulfed cells was believed to be executed non-autonomously by the engulfing cells, so CIC structures are believed to mediate a novel type of cell death process that parallels the existing cell-autonomous death processes apoptosis, necrosis, and autosis (7). Entosis is the best studied mechanism underlying the formation of CIC structures between tumor cells, and it is driven by polarized actomyosin that is compartmentalized by p190A RhoGAP recruited to Ecadherin-mediated adherens junction (8,9).…”

Section: Introductionmentioning

confidence: 99%

High Frequency of Cell-in-Cell Formation in Heterogeneous Human Breast Cancer Tissue in a Patient With Poor Prognosis: A Case Report and Literature Review

Ruan

Niu²,

Jiang

et al. 2019

Front. Oncol.

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Cell cannibalism is a unique pathological phenomenon that has been observed at low frequency in a variety of human tumor samples (<0.5%), including breast cancer. Cannibalistic cells typically form cell-in-cell (CIC) structures characterized by enclosure of one cell or more by another, mediating a novel type of cell death "entosis," which was proposed as the type IV cell death. A large number of CIC structures are generally associated with malignant transformation and progression, and they are believed to be primed by and form among heterogeneous cells. However, there is currently no in vivo evidence from human tumor samples. In this case report, covering a 37-year-old female breast cancer patient, we observed considerable heterogeneity and proliferative activity (>70% Ki-67 positivity) in her breast cancer cells, accompanied by high frequency of CIC formation (∼6%) and poor prognosis. We consider this a typical example of cell cannibalism, supporting a role of heterogeneity in cell-in-cell formation and malignant progression. It may serve as a pretest basis for further investigations of cell-in-cell biology and breast cancer treatment.

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“…Due to the lack of evidence pertaining to specific cellular fate, and the possibility for cells to escape entotic engulfment, it has now been proposed that entosis be referred to as a mode of internalisation only, and not a complete mode of cell death. In contrast, Perfettini et al have recently suggested that entotic cell death be classified as type IV non-cell autonomous cell death [78]. It becomes clear that future work is required that enables precise relation of autophagic activity with the diversity of lethal autophagic responses.…”

Section: The Molecular Distinction Between Adcd and Autosismentioning

confidence: 98%

The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

Kriel

Loos

2019

Cell Death Differ

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The recent discovery of autosis as a variant of autophagy-dependent cell death has challenged the conventional understanding of cell death and programmed cell death in cellular decision making. In contrast to previous accounts of distinct cell death modalities, autosis occurs with high autophagic activity, in the absence of apoptotic and necrotic markers and yet is not fully regulated by typical autophagy markers. Given the metabolic importance of autophagic responses and the extensive cross-talk with both apoptosis and necrosis signalling, the classical and morphotype-driven characterization of cell death as pre-determined subroutines is being increasingly called into question. Furthermore, the conflicting evidence with regards to cell death induction through autophagy modulation in various cancer models highlights the lack of consensus over the extent to which autophagy assists in cell death ontrol and whether it is capable of being a bona fide lethal process. This review evaluates the evidence and context of autophagy-dependent cell death and delineates the role of an autophagic flux threshold associated with 'lethal' and 'non-lethal' autophagy and its role in autosis control. In doing so, cancer treatment avenues will be explored with regards to precision modulation of tumour autophagic flux to ascertain whether autosis induction may present a novel therapeutic strategy.

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Entosis: The emerging face of non-cell-autonomous type IV programmed death

Cited by 45 publications

References 76 publications

Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation

Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation

High Frequency of Cell-in-Cell Formation in Heterogeneous Human Breast Cancer Tissue in a Patient With Poor Prognosis: A Case Report and Literature Review

The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

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