Search

Resistance to chemotherapy remains the main challenge for cancer treatment. One of the mechanisms of tumor escape from cytotoxic agents could be the formation of cell-in-cell (CIC) structures, in which the outer cell protects the inner cell from unfavorable environment. Such structures have been found in many tumor types, however, their link to chemosensitivity is elusive. Here, we tested whether the CIC structures can promote resistance of colorectal cancer cells to chemotherapy. To identify CIC structures in cell cultures and in tumor xenografts, both transmission electron microscopy and confocal fluorescence microscopy of live and fixed cells as well as tissue slices and histopathology were used. Cytogenetic analysis was performed to detect chromosome instability associated with the drug resistance. It was found that in the five colorectal cancer cell lines intrinsic chemoresistance positively correlated with the ability of cells to spontaneously form CIC structures. Cultured cells treated with oxaliplatin and Irinotecan and tumor xenografts treated with FOLFOX or FOLFIRI regimens displayed an increased number of CICs after the treatment. The release of the inner cell from CIC structure was observed after removal of the drug. The number of CICs in the cell lines and tumors with acquired resistance to oxaliplatin was higher than in the drug-naive counterparts. The development of chemoresistance was also accompanied by the changes in the cell's ploidy. These preliminary data clearly demonstrate the associations of CIC structures with chemoresistance of colorectal cancer in cultured cells and tumor xenografts and show the prospect of further clinical validation of CICs as a potential prognostic marker for treatment efficiency. [ABSTRACT FROM AUTHOR]

Objective: In 2007, entosis was proposed as a form of programmed cell death, distinct from apoptosis. This process involves a living cell (internalized cell) actively invading a neighboring live cell of the same type (host cell), forming a cell-in-cell structure. Recently, entosis has been increasingly associated with cancer, leading to significant advancements in research. Despite this progress, a comprehensive and unbiased review of the current state of entosis research is lacking. This study aims to evaluate the developments in the field of entosis over the past decade and highlight emerging research trends. Materials and methods: We performed a literature search for studies published since the introduction of the entosis concept, using the Web of Science Core Collection database. The bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel, and the Bibliometrix R package. Results: A total of 196 articles from 39 countries and 346 institutions were included. Between 2007 and 2024, research on entosis has seen rapid growth, with most publications originating from China and the United States. The United States also leads in total citations, with Memorial Sloan Kettering Cancer Center emerging as the top research institution. Sun Qiang is the most prolific author in this field, while Overholtzer M has the highest number of citations. Current Molecular Medicine has published the most articles related to entosis. Frequently occurring keywords include "entosis," "cannibalism," "autophagy," and "apoptosis." In recent years, keywords such as "phagocytosis," "drug resistance," and "human cancers" have surged, indicating a growing focus on understanding the role of entosis in tumor progression and exploring its potential as a therapeutic target for cancer treatment. Conclusions: This study provides the first bibliometric analysis of entosis, detailing its evolution over the last decade. It highlights critical areas of interest, including the development of inhibitors targeting entosis and their potential clinical applications. This research aims to guide future investigations and serve as a valuable resource for scholars exploring entosis in cancer biology. [ABSTRACT FROM AUTHOR]

Entosis, a form of cell cannibalism, is a newly discovered pathogenic mechanism leading to the development of small brains, termed microcephaly, in which P53 activation was found to play a major role. Microcephaly with entosis, found in Pals1 mutant mice, displays P53 activation that promotes entosis and apoptotic cell death. This previously unappreciated pathogenic mechanism represents a novel cellular dynamic in dividing cortical progenitors which is responsible for cell loss. To date, various recent models of microcephaly have bolstered the importance of P53 activation in cell death leading to microcephaly. P53 activation caused by mitotic delay or DNA damage manifests apoptotic cell death which can be suppressed by P53 removal in these animal models. Such genetic studies attest P53 activation as quality control meant to eliminate genomically unfit cells with minimal involvement in the actual function of microcephaly associated genes. In this review, we summarize the known role of P53 activation in a variety of microcephaly models and introduce a novel mechanism wherein entotic cell cannibalism in neural progenitors is triggered by P53 activation. [ABSTRACT FROM AUTHOR]

ObjectiveIn 2007, entosis was proposed as a form of programmed cell death, distinct from apoptosis. This process involves a living cell (internalized cell) actively invading a neighboring live cell of the same type (host cell), forming a cell-in-cell structure. Recently, entosis has been increasingly associated with cancer, leading to significant advancements in research. Despite this progress, a comprehensive and unbiased review of the current state of entosis research is lacking. This study aims to evaluate the developments in the field of entosis over the past decade and highlight emerging research trends.Materials and methodsWe performed a literature search for studies published since the introduction of the entosis concept, using the Web of Science Core Collection database. The bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel, and the Bibliometrix R package.ResultsA total of 196 articles from 39 countries and 346 institutions were included. Between 2007 and 2024, research on entosis has seen rapid growth, with most publications originating from China and the United States. The United States also leads in total citations, with Memorial Sloan Kettering Cancer Center emerging as the top research institution. Sun Qiang is the most prolific author in this field, while Overholtzer M has the highest number of citations. Current Molecular Medicine has published the most articles related to entosis. Frequently occurring keywords include “entosis,” “cannibalism,” “autophagy,” and “apoptosis.” In recent years, keywords such as “phagocytosis,” “drug resistance,” and “human cancers” have surged, indicating a growing focus on understanding the role of entosis in tumor progression and exploring its potential as a therapeutic target for cancer treatment.ConclusionsThis study provides the first bibliometric analysis of entosis, detailing its evolution over the last decade. It highlights critical areas of interest, including the development of inhibitors targeting entosis and their potential clinical applications. This research aims to guide future investigations and serve as a valuable resource for scholars exploring entosis in cancer biology.

Diabetes mellitus is a metabolic disease caused by disorders of insulin secretion and utilization. Long-term hyperglycemia, insulin resistance, and disorders of glucose and lipid metabolism cause vascular endothelial cell damage. Endothelial dysfunction is a key feature of diabetic vascular complications such as diabetic nephropathy, retinopathy, neuropathy, and atherosclerosis. Importantly, cell death is thought to be a key factor contributing to vascular endothelial injury. Morphologically, cell death can be divided into three forms: type I apoptosis, type II autophagy, and type III necrosis. According to the difference in function, cell death can be divided into accidental cell death (ACD) and regulated cell death (RCD). RCD is a controlled process involving numerous proteins and precise signaling cascades. Multiple subroutines covered by RCD may be involved in diabetic endothelial dysfunction, including apoptosis, autophagy, necroptosis, pyroptosis, entosis, ferroptosis, ferroautophagy, parthanatos, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, cuproptosis, and PANoptosis. This article briefly reviews the mechanism and significance of cell death associated with diabetic endothelial dysfunction, which will help deepen the understanding of diabetic endothelial cell death and provide new therapeutic ideas.

One of the regulated forms of cell death is the cell-in-cell (CIC) structure, in which a surviving cell is engulfed by another cell, a mechanism that causes the death of the engulfed cell by an adjacent cell. Several investigators have previously shown that the presence of CICs is an independent risk factor significantly associated with decreased survival in patients with various types of cancer. In this review, we summarize the role of CIC in the tumor microenvironment (TME), including changes and crosstalk of molecules and proteins in the surrounding CIC, and the role of these factors in contributing to therapeutic resistance acquisition. Moreover, CIC structure formation is influenced by the modulation of TME, which may lead to changes in cellular properties. Future use of CIC as a clinical diagnostic tool will require a better understanding of the effects of chemotherapy on CIC, biomarkers for each CIC formation process, and the development of automated CIC detection methods in tissue sections of tumor specimens. [ABSTRACT FROM AUTHOR]

TiO2 nanoparticles are widely used in industry, pharmacology, and medicine. Recently, it has been proposed to use TiO2 nanoparticles for targeted delivery of chemotherapeutic drugs, which can lead to an increase in the local concentration of TiO2 and influence the processes occurring in the tumor, including entosis (the invasion of one tumor cell into another). In this work, we studied the effect of TiO2 nanoparticles (particles of the mineral anatase less than 25 nm in size and particles consisting of a mixture of anatase and rutile less than 75 nm in size at a concentration of 1, 10, or 100 μg/mL for 72 h) on the process of entosis in human breast MCF-7 adenocarcinoma cell culture. Cultivation of cells in the presence of different types of TiO2 nanoparticles slows down proliferation and causes a decrease in the number of entoses. Elemental analysis by analytical electron microscopy revealed the presence of TiO2 in the endosomal compartment, in the cytosol and in the extracellular space. Immunochemical staining showed that both types of TiO2 nanoparticles at a concentration of 10 μg/mL disrupt the formation of adhesive contacts, including those in the early stages of entosis. The impact of anatase particles induces the translocation of the p53 protein into the cell nuclei. In general, the TiO2 nanoparticles used in the work inhibit entosis in MCF-7 culture cells, disrupting adhesive contacts and interfering with the process of invasion. However, it can be assumed that disruption of adhesive contacts can enhance the mobility of tumor cells and metastasis. [ABSTRACT FROM AUTHOR]

This review summarizes information about cell-in-cell (CIC) structures with a focus on gastrointestinal tumors. The phenomenon when one cell lives in another one has attracted an attention of researchers over the past decades. We briefly discuss types of CIC structures and mechanisms of its formation, as well as the biological basis and consequences of the cell-engulfing process. Numerous clinico-histopathological studies demonstrate the significance of these structures as prognostic factors, mainly correlated with negative prognosis. The presence of CIC structures has been identified in all gastrointestinal tumors. However, the majority of studies concern pancreatic cancer. In this field, in addition to the assessment of the prognostic markers, the attempts to manipulate the ability of cells to form CISs have been done in order to stimulate the death of the inner cell. Number of CIC structures also correlates with genetic features for some gastrointestinal tu-mors. The role of CIC structures in the responses of tumors to therapies, both chemotherapy and immunotherapy, seems to be the most poorly studied. However, there is some evidence of involvement of CIC structures in treatment failure. Here, we summarized the current literature on CIC structures in cancer with a focus on gastrointestinal tumors and specified future perspectives for investigation. [ABSTRACT FROM AUTHOR]

Regulated Cell Death (RCD) is a mode of cell death that occurs through drug or genetic intervention. The regulation of RCDs is one of the significant reasons for the long survival time of tumor cells and poor prognosis of patients. Long noncoding RNAs (lncRNAs) which are involved in the regulation of tumor biological processes, including RCDs occurring on tumor cells, are closely related to tumor progression. In this review, we describe the mechanisms of eight different RCDs which contain apoptosis, necroptosis, pyroptosis, NETosis, entosis, ferroptosis, autosis and cuproptosis. Meanwhile, their respective roles in the tumor are aggregated. In addition, we outline the literature that is related to the regulatory relationships between lncRNAs and RCDs in tumor cells, which is expected to provide new ideas for tumor diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Entosis is a non‐apoptotic cell death process that forms characteristic cell‐in‐cell structures in cancers, killing invading cells. Intracellular Ca2+ dynamics are essential for cellular processes, including actomyosin contractility, migration, and autophagy. However, the significance of Ca2+ and Ca2+ channels participating in entosis is unclear. Here, it is shown that intracellular Ca2+ signaling regulates entosis via SEPTIN‐Orai1‐Ca2+/CaM‐MLCK‐actomyosin axis. Intracellular Ca2+ oscillations in entotic cells show spatiotemporal variations during engulfment, mediated by Orai1 Ca2+ channels in plasma membranes. SEPTIN controlled polarized distribution of Orai1 for local MLCK activation, resulting in MLC phosphorylation and actomyosin contraction, leads to internalization of invasive cells. Ca2+ chelators and SEPTIN, Orai1, and MLCK inhibitors suppress entosis. This study identifies potential targets for treating entosis‐associated tumors, showing that Orai1 is an entotic Ca2+ channel that provides essential Ca2+ signaling and sheds light on the molecular mechanism underlying entosis that involves SEPTIN filaments, Orai1, and MLCK. [ABSTRACT FROM AUTHOR]

Abstract Entosis is a non‐apoptotic cell death process that forms characteristic cell‐in‐cell structures in cancers, killing invading cells. Intracellular Ca2+ dynamics are essential for cellular processes, including actomyosin contractility, migration, and autophagy. However, the significance of Ca2+ and Ca2+ channels participating in entosis is unclear. Here, it is shown that intracellular Ca2+ signaling regulates entosis via SEPTIN‐Orai1‐Ca2+/CaM‐MLCK‐actomyosin axis. Intracellular Ca2+ oscillations in entotic cells show spatiotemporal variations during engulfment, mediated by Orai1 Ca2+ channels in plasma membranes. SEPTIN controlled polarized distribution of Orai1 for local MLCK activation, resulting in MLC phosphorylation and actomyosin contraction, leads to internalization of invasive cells. Ca2+ chelators and SEPTIN, Orai1, and MLCK inhibitors suppress entosis. This study identifies potential targets for treating entosis‐associated tumors, showing that Orai1 is an entotic Ca2+ channel that provides essential Ca2+ signaling and sheds light on the molecular mechanism underlying entosis that involves SEPTIN filaments, Orai1, and MLCK.

Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways include apoptosis, a form of programmed cell death controlled by a well-defined biochemical pathway, and necrosis, the lysis of acutely injured cells. New types of regulated cell death include necroptosis, pyroptosis, ferroptosis, phagoptosis, and entosis. Autophagy can promote survival or can cause death. Newly described processes of anastasis and resuscitation show that, remarkably, cells can recover from the brink of apoptosis or necroptosis. Important new work shows that epithelia achieve homeostasis by extruding excess cells, which then die by anoikis due to loss of survival signals. This mechanically regulated process both maintains barrier function as cells die and matches rates of proliferation and death. In this review, we describe these unconventional ways in which cells have evolved to die or survive, as well as the contributions that these processes make to homeostasis and cancer.

Phenotypic characteristics of human non-small cell lung cancer cells, A549 (p53 wild-type) and H1299 (p53-deficient) as well as their descendants surviving after multifraction X-ray irradiation at a cumulative dose of 60 Gy (sublines A549HR and H1299HR, respectively) were studied before and after additional 2 Gy single dose irradiation. In 24 h after the additional irradiation, we observed a significant increase in the proportion of cells with signs of entosis (by 5 times, p<0.05) and SA-β-gal+ cells (by 1.6 times, p<0.01) in the general population of A549HR cells. In contrast, a significant increase in the proportion of only SA-β-gal+ multinucleated giant cancer cells was revealed in the parental A549 cells. Additional single dose irradiation resulted in a significant (by 1.8 times, p<0.05) increase in the proportion of multinucleated giant cancer cells in H1299HR cells in comparison with their parental H1299 cells. These changes did not correlate with changes in the proportion of entotic cells, because their high basal content in the absence of functional p53 did not change in response to additional single dose irradiation. At the same time, both p53-deficient non-small cell lung cancer cell lines showed a significant (2.9-fold for H1299 and 5.5-fold for H1299HR cells, p<0.001) increase in the proportion of SA-β-gal+ cells in the general population, but not in the multinucleated giant cancer cells population. [ABSTRACT FROM AUTHOR]

Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhibiting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity.

For over a century, cells within other cells have been detected by pathologists as common histopathological findings in tumors, being generally identified as "cell-in-cell" structures. Despite their characteristic morphology, these structures can originate from various processes, such as cannibalism, entosis and emperipolesis. However, only in the last few decades has more attention been given to these events due to their importance in tumor development. In cancers such as oral squamous cell carcinoma, cell-in-cell events have been linked to aggressiveness, metastasis, and therapeutic resistance. This review aims to summarize relevant information about the occurrence of various cell-in-cell phenomena in the context of oral squamous cell carcinoma, addressing their causes and consequences in cancer. The lack of a standard terminology in diagnosing these events makes it difficult to classify the existing cases and to map the behavior and impacts of these structures. Despite being frequently reported in oral squamous cell carcinoma and other cancers, their impacts on carcinogenesis aren't fully understood. Cell-in-cell formation is seen as a survival mechanism in the face of a lack of nutritional availability, an acid microenvironment and potential harm from immune cell defense. In this deadly form of competition, cells that engulf other cells establish themselves as winners, taking over as the predominant and more malignant cell population. Understanding the link between these structures and more aggressive behavior in oral squamous cell carcinoma is of paramount importance for their incorporation as part of a therapeutic strategy. [ABSTRACT FROM AUTHOR]

Whereas biochemical markers are available for most types of cell death, current studies on non-autonomous cell death by entosis rely strictly on the identification of cell-in-cell structures (CICs), a unique morphological readout that can only be quantified manually at present. Moreover, the manual CIC quantification is generally over-simplified as CIC counts, which represents a major hurdle against profound mechanistic investigations. In this study, we take advantage of artificial intelligence technology to develop an automatic identification method for CICs (AIM-CICs), which performs comprehensive CIC analysis in an automated and efficient way. The AIM-CICs, developed on the algorithm of convolutional neural network, can not only differentiate between CICs and non-CICs (the area under the receiver operating characteristic curve (AUC) > 0.99), but also accurately categorize CICs into five subclasses based on CIC stages and cell number involved (AUC > 0.97 for all subclasses). The application of AIM-CICs would systemically fuel research on CIC-mediated cell death, such as high-throughput screening. [ABSTRACT FROM AUTHOR]

Entosis is a mechanism of cell death that involves neighbor cell ingestion. This process occurs in cancers and promotes a form of cell competition, where winner cells engulf and kill losers. Entosis is driven by a mechanical differential that allows softer cells to eliminate stiffer cells. While this process can be induced by matrix detachment, whether other stressors can activate entosis is unknown. Here, we find that entosis is induced in adherent cells by glucose withdrawal. Glucose withdrawal leads to a bimodal distribution of cells based on their deformability, where stiffer cells appear in a manner requiring the energy-sensing AMP-activated protein kinase (AMPK). We show that loser cells with high levels of AMPK activity are eliminated by winners through entosis, which supports winner cell proliferation under nutrient-deprived conditions. Our findings demonstrate that entosis serves as a cellular response to metabolic stress that enables nutrient recovery through neighbor cell ingestion.

For over a century, cells within other cells have been detected by pathologists as common histopathological findings in tumors, being generally identified as “cell-in-cell” structures. Despite their characteristic morphology, these structures can originate from various processes, such as cannibalism, entosis and emperipolesis. However, only in the last few decades has more attention been given to these events due to their importance in tumor development. In cancers such as oral squamous cell carcinoma, cell-in-cell events have been linked to aggressiveness, metastasis, and therapeutic resistance. This review aims to summarize relevant information about the occurrence of various cell-in-cell phenomena in the context of oral squamous cell carcinoma, addressing their causes and consequences in cancer. The lack of a standard terminology in diagnosing these events makes it difficult to classify the existing cases and to map the behavior and impacts of these structures. Despite being frequently reported in oral squamous cell carcinoma and other cancers, their impacts on carcinogenesis aren’t fully understood. Cell-in-cell formation is seen as a survival mechanism in the face of a lack of nutritional availability, an acid microenvironment and potential harm from immune cell defense. In this deadly form of competition, cells that engulf other cells establish themselves as winners, taking over as the predominant and more malignant cell population. Understanding the link between these structures and more aggressive behavior in oral squamous cell carcinoma is of paramount importance for their incorporation as part of a therapeutic strategy.

BAP1 -inactivated melanocytoma (BIM) is a novel subgroup of melanocytic neoplasm listed in the 5th edition of WHO classification of skin tumor. BIM is characterized by two molecular alterations, including a mitogenic driver mutation (usually BRAF gene) and the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, which encodes for BRCA1-associated protein (BAP1). The latter represents a nuclear-localized deubiquitinase involved in several cellular processes including cell cycle regulation, chromatin remodeling, DNA damage response, differentiation, senescence and cell death. BIMs are histologically characterized by a population of large epithelioid melanocytes with well-demarcated cytoplasmic borders and copious eosinophilic cytoplasm, demonstrating loss of BAP1 nuclear expression by immunohistochemistry. Recently, we have published a series of 50 cases, extending the morphological spectrum of the neoplasm and highlighting some new microscopic features. In the current article, we focus on some new histological features, attempting to explain and link them to certain mechanisms of tumor development, including senescence, endoreplication, endocycling, asymmetric cytokinesis, entosis and others. In light of the morphological and molecular findings observed in BIM, we postulated that this entity unmasks a fine mechanism of tumor in which both clonal/stochastic and hierarchical model can be unified. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Non-professional phagocytosis is usually triggered by stimuli such as necrotic cell death. In tumor therapy, the tumors often disappear slowly and only long time after the end of therapy. Here, tumor therapy inactivates the cells by inducing senescence. Therefore, study focused whether senescence is a stimulus for non-professional phagocytosis or whether senescent cells themselves phagocytize non-professionally. Results Senescence was induced in cell lines by camptothecin and a phagocytosis assay was performed. In tissue of a cohort of 192 rectal cancer patients senescence and non-professional phagocytosis was studied by anti-histone H3K9me3 and anti-E-cadherin staining. Senescent fibroblasts and pancreas carcinoma cells phagocytize necrotic cells but are not phagocytized. In the tissue of rectal carcinoma, senescent cells can phagocytize and can be phagocytized. A high number of senescent cells and, at the same time, high numbers of non-professional phagocytizing cells in the rectal carcinoma tissue lead to an extremely unfavorable prognosis regarding overall survival. Conclusion Senescent cells can be non-professionally phagocytized and at the same time they can non-professionally phagocytize in vivo. In vitro experiments indicate that it is unlikely that senescence is a strong trigger for non-professional phagocytosis. Combined high rates of non-professional phagocytosis and high rates of senescence are an extremely poor prognostic factor for overall survival.

Abstract Epithelial ovarian cancer (EOC) is one of the leading causes of death from gynecologic cancers and peritoneal dissemination is the major cause of death in patients with EOC. Although the loss of 4.1N is associated with increased risk of malignancy, its association with EOC remains unclear. To explore the underlying mechanism of the loss of 4.1N in constitutive activation of epithelial-mesenchymal transition (EMT) and matrix-detached cell death resistance, we investigated samples from 268 formalin-fixed EOC tissues and performed various in vitro and in vivo assays. We report that the loss of 4.1N correlated with progress in clinical stage, as well as poor survival in EOC patients. The loss of 4.1N induces EMT in adherent EOC cells and its expression inhibits anoikis resistance and EMT by directly binding and accelerating the degradation of 14-3-3 in suspension EOC cells. Furthermore, the loss of 4.1N could increase the rate of entosis, which aggravates cell death resistance in suspension EOC cells. Moreover, xenograft tumors in nude mice also show that the loss of 4.1N can aggravate peritoneal dissemination of EOC cells. Single-agent and combination therapy with a ROCK inhibitor and a 14-3-3 antagonist can reduce tumor spread to varying degrees. Our results not only define the vital role of 4.1N loss in inducing EMT, anoikis resistance, and entosis-induced cell death resistance in EOC, but also suggest that individual or combined application of 4.1N, 14-3-3 antagonists, and entosis inhibitors may be a promising therapeutic approach for the treatment of EOC.

Metastasis is one of the key concepts in modern oncology, which connects the movement of cancer cells in the body with changes in their characteristics and functions. The review examines the main aspects of metastasis, including theories, facts and discoveries that help to better understand this phenomenon and develop new approaches to its treatment. In this article, we also proposed the theory of cell fusion with the formation of hybrid cells as one of the factors of metastasis. We believe that the fusion of tumor cells with other types of motile cells (leukocytes and bone marrow progenitor cells) may represent an additional mechanism of tumor spread. Cells of bone marrow origin, including cells of the myeloid and macrophage lineages, are the best candidates for heterotypic fusion in regenerative conditions. Events such as cell fusion may play a role in tumor dedifferentiation and progression. We presented a number of arguments and data from our own research that speak in favor of the proposed theory. It should be noted that if the fusion of a normal cell with a tumor cell is one of the possible triggers of tumorigenesis and cancer spread, the mechanisms underlying this process may provide possible new targets for treatment. Therefore, their analysis will expand our arsenal of therapeutic tools by adding completely new targets - cell signaling molecules - and will provide the impetus for reconsidering the tumor microenvironment from a different angle., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Metabolic stress contributes to the regulation of cell death in normal and diseased tissues. While different forms of cell death are known to be regulated by metabolic stress, how the cell engulfment and killing mechanism entosis is regulated is not well understood. Here we find that the death of entotic cells is regulated by the presence of amino acids and activity of the mechanistic target of rapamycin (mTOR). Amino acid withdrawal or mTOR inhibition induces apoptosis of engulfed cells and blocks entotic cell death that is associated with the lipidation of the autophagy protein microtubule‐associated protein light chain 3 (LC3) to entotic vacuoles. Two other live cell engulfment programs, homotypic cell cannibalism (HoCC) and anti‐CD47 antibody‐mediated phagocytosis, known as phagoptosis, also undergo a similar vacuole maturation sequence involving LC3 lipidation and lysosome fusion, but only HoCC involves mTOR‐dependent regulation of vacuole maturation and engulfed cell death similar to entosis. We further find that the regulation of cell death by mTOR is independent of autophagy activation and instead involves the 4E‐BP1/2 proteins that are known regulators of mRNA translation. Depletion of 4E‐BP1/2 proteins can restore the mTOR‐regulated changes of entotic death and apoptosis rates of engulfed cells. These results identify amino acid signaling and the mTOR‐4E‐BP1/2 pathway as an upstream regulation mechanism for the fate of live engulfed cells formed by entosis and HoCC. [ABSTRACT FROM AUTHOR]

Cell-in-cell (CIC) structures are defined as the special structures with one or more cells enclosed inside another one. Increasing data indicated that CIC structures were functional surrogates of complicated cell behaviors and prognosis predictor in heterogeneous cancers. However, the CIC structure profiling and its prognostic value have not been reported in human esophageal squamous cell Carcinoma (ESCC). We conducted the analysis of subtyped CIC-based profiling in ESCC using “epithelium-macrophage-leukocyte” (EML) multiplex staining and examined the prognostic value of CIC structure profiling through Kaplan-Meier plotting and Cox regression model. Totally, five CIC structure subtypes were identified in ESCC tissue and the majority of them was homotypic CIC (hoCIC) with tumor cells inside tumor cells (TiT). By univariate and multivariate analyses, TiT was shown to be an independent prognostic factor for resectable ESCC, and patients with higher density of TiT tended to have longer post-operational survival time. Furthermore, in subpopulation analysis stratified by TNM stage, high TiT density was associated with longer overall survival (OS) in patients of TNM stages III and IV as compared with patients with low TiT density (mean OS: 51 vs 15 months, P = 0.04) and T3 stage (mean OS: 57 vs 17 months, P=0.024). Together, we reported the first CIC structure profiling in ESCC and explored the prognostic value of subtyped CIC structures, which supported the notion that functional pathology with CIC structure profiling is an emerging prognostic factor for human cancers, such as ESCC.

Balancing cell survival and cell death is fundamental to development and homeostasis. Cell death is regulated by multiple interconnected signaling pathways and molecular mechanisms. Regulated cell death (RCD) is implicated in fundamental processes such as organogenesis and tissue remodeling, removal of unnecessary structures or cells, and regulation of cell numbers. RCD can also be triggered by exogenous perturbations of the intracellular or extracellular microenvironment when the adaptive processes that respond to stress fail. During the past few years, many novel forms of non-apoptotic RCD have been identified, and the characterization of RCD mechanisms at a molecular level has deepened our understanding of diseases encountered in human and veterinary medicine. Given the complexity of these processes, it has become clear that the identification of RCD cannot be based simply on morphologic characteristics and that descriptive and diagnostic terms presently used by pathologists—such as individual cell apoptosis or necrosis—appear inadequate and possibly misleading. In this review, the current understanding of the molecular machinery of each type of non-apoptotic RCD mechanisms is outlined. Due to the continuous discovery of new mechanisms or nuances of previously described processes, the limitations of the terms apoptosis and necrosis to indicate microscopic findings are also reported. In addition, the need for a standard panel of biomarkers and functional tests to adequately characterize the underlying RCD and its role as a mechanism of disease is considered. [ABSTRACT FROM AUTHOR]

Cell-in-cell (CIC) structures are defined as the special structures with one or more cells enclosed inside another one. Increasing data indicated that CIC structures were functional surrogates of complicated cell behaviors and prognosis predictor in heterogeneous cancers. However, the CIC structure profiling and its prognostic value have not been reported in human esophageal squamous cell Carcinoma (ESCC). We conducted the analysis of subtyped CIC-based profiling in ESCC using "epithelium-macrophage-leukocyte" (EML) multiplex staining and examined the prognostic value of CIC structure profiling through Kaplan-Meier plotting and Cox regression model. Totally, five CIC structure subtypes were identified in ESCC tissue and the majority of them was homotypic CIC (hoCIC) with tumor cells inside tumor cells (TiT). By univariate and multivariate analyses, TiT was shown to be an independent prognostic factor for resectable ESCC, and patients with higher density of TiT tended to have longer post-operational survival time. Furthermore, in subpopulation analysis stratified by TNM stage, high TiT density was associated with longer overall survival (OS) in patients of TNM stages III and IV as compared with patients with low TiT density (mean OS: 51 vs 15 months, P = 0.04) and T3 stage (mean OS: 57 vs 17 months, P =0.024). Together, we reported the first CIC structure profiling in ESCC and explored the prognostic value of subtyped CIC structures, which supported the notion that functional pathology with CIC structure profiling is an emerging prognostic factor for human cancers, such as ESCC. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is one of the leading causes of death from gynecologic cancers and peritoneal dissemination is the major cause of death in patients with EOC. Although the loss of 4.1N is associated with increased risk of malignancy, its association with EOC remains unclear. To explore the underlying mechanism of the loss of 4.1N in constitutive activation of epithelial-mesenchymal transition (EMT) and matrix-detached cell death resistance, we investigated samples from 268 formalin-fixed EOC tissues and performed various in vitro and in vivo assays. We report that the loss of 4.1N correlated with progress in clinical stage, as well as poor survival in EOC patients. The loss of 4.1N induces EMT in adherent EOC cells and its expression inhibits anoikis resistance and EMT by directly binding and accelerating the degradation of 14-3-3 in suspension EOC cells. Furthermore, the loss of 4.1N could increase the rate of entosis, which aggravates cell death resistance in suspension EOC cells. Moreover, xenograft tumors in nude mice also show that the loss of 4.1N can aggravate peritoneal dissemination of EOC cells. Single-agent and combination therapy with a ROCK inhibitor and a 14-3-3 antagonist can reduce tumor spread to varying degrees. Our results not only define the vital role of 4.1N loss in inducing EMT, anoikis resistance, and entosis-induced cell death resistance in EOC, but also suggest that individual or combined application of 4.1N, 14-3-3 antagonists, and entosis inhibitors may be a promising therapeutic approach for the treatment of EOC. [ABSTRACT FROM AUTHOR]

Summary: Entosis is a cell-in-cell (CIC)-mediated death program. Contractile actomyosin (CA) and the adherens junction (AJ) are two core elements essential for entotic CIC formation, but the molecular structures interfacing them remain poorly understood. Here, we report the characterization of a ring-like structure interfacing between the peripheries of invading and engulfing cells. The ring-like structure is a multi-molecular complex consisting of adhesive and cytoskeletal proteins, in which the mechanical sensor vinculin is highly enriched. The vinculin-enriched structure senses mechanical force imposed on cells, as indicated by fluorescence resonance energy transfer (FRET) analysis, and is thus termed the mechanical ring (MR). The MR actively interacts with CA and the AJ to help establish and maintain polarized actomyosin that drives cell internalization. Vinculin depletion leads to compromised MR formation, CA depolarization, and subsequent CIC failure. In summary, we suggest that the vinculin-enriched MR, in addition to CA and AJ, is another core element essential for entosis.

The liver is our largest internal organ and it plays major roles in drug detoxification and immunity, where the ingestion of extracellular material through phagocytosis is a critical pathway. Phagocytosis is the deliberate endocytosis of large particles, microbes, dead cells or cell debris and can lead to cell-in-cell structures. Various types of cell endocytosis have been recently described for hepatic epithelia (hepatocytes), which are non-professional phagocytes. Given that up to 80% of the liver comprises hepatocytes, the biological impact of cell-in-cell structures in the liver can have profound effects in liver regeneration, inflammation and cancer. This review brings together the latest reports on four types of endocytosis in the liver -efferocytosis, entosis, emperipolesis and enclysis, with a focus on hepatocyte biology.

Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes mellitus, characterized by abnormalities of myocardial structure and function. Researches on the models of type 1 and type 2 diabetes mellitus as well as the application of genetic engineering technology help in understanding the molecular mechanism of DCM. DCM has multiple hallmarks, including hyperglycemia, insulin resistance, increased free radical production, lipid peroxidation, mitochondrial dysfunction, endothelial dysfunction, and cell death. Essentially, cell death is considered to be the terminal pathway of cardiomyocytes during DCM. Morphologically, cell death can be classified into four different forms: apoptosis, autophagy, necrosis, and entosis. Apoptosis, as type I cell death, is the fastest form of cell death and mainly occurs depending on the caspase proteolytic cascade. Autophagy, as type II cell death, is a degradation process to remove damaged proteins, dysfunctional organelles and commences by the formation of autophagosome. Necrosis is type III cell death, which contains a great diversity of cell death processes, such as necroptosis and pyroptosis. Entosis is type IV cell death, displaying “cell-in-cell” cytological features and requires the engulfing cells to execute. There are also some other types of cell death such as ferroptosis, parthanatos, netotic cell death, lysosomal dependent cell death, alkaliptosis or oxeiptosis, which are possibly involved in DCM. Drugs or compounds targeting the signals involved in cell death have been used in clinics or experiments to treat DCM. This review briefly summarizes the mechanisms and implications of cell death in DCM, which is beneficial to improve the understanding of cell death in DCM and may propose novel and ideal strategies in future.

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.

Cell cannibalism is a unique pathological phenomenon that has been observed at low frequency in a variety of human tumor samples (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.

Background: Non-professional phagocytosis is usually triggered by stimuli such as necrotic cell death. In tumor therapy, the tumors often disappear slowly and only long time after the end of therapy. Here, tumor therapy inactivates the cells by inducing senescence. Therefore, study focused whether senescence is a stimulus for non-professional phagocytosis or whether senescent cells themselves phagocytize non-professionally. Results: Senescence was induced in cell lines by camptothecin and a phagocytosis assay was performed. In tissue of a cohort of 192 rectal cancer patients senescence and non-professional phagocytosis was studied by anti-histone H3K9me3 and anti-E-cadherin staining. Senescent fibroblasts and pancreas carcinoma cells phagocytize necrotic cells but are not phagocytized. In the tissue of rectal carcinoma, senescent cells can phagocytize and can be phagocytized. A high number of senescent cells and, at the same time, high numbers of non-professional phagocytizing cells in the rectal carcinoma tissue lead to an extremely unfavorable prognosis regarding overall survival. Conclusion: Senescent cells can be non-professionally phagocytized and at the same time they can non-professionally phagocytize in vivo. In vitro experiments indicate that it is unlikely that senescence is a strong trigger for non-professional phagocytosis. Combined high rates of non-professional phagocytosis and high rates of senescence are an extremely poor prognostic factor for overall survival. [ABSTRACT FROM AUTHOR]

Several lines of evidence indicate that cell competition can occur in mammals. In particular, at the initial stage of carcinogenesis, normal epithelial cells are able to recognize the neighboring transformed cells and actively eliminate them from epithelial tissues. This implies that normal epithelia have anti-tumor activity that does not involve immune cells, which is termed epithelial defense against cancer (EDAC). In this review article, we summarize recent advances on the underlying molecular machinery of EDAC. In addition, we also describe the molecular mechanisms by which transformed cells escape from EDAC to promote carcinogenesis. [ABSTRACT FROM AUTHOR]

The liver is our largest internal organ and it plays major roles in drug detoxification and immunity, where the ingestion of extracellular material through phagocytosis is a critical pathway. Phagocytosis is the deliberate endocytosis of large particles, microbes, dead cells or cell debris and can lead to cell-in-cell structures. Various types of cell endocytosis have been recently described for hepatic epithelia (hepatocytes), which are non-professional phagocytes. Given that up to 80% of the liver comprises hepatocytes, the biological impact of cell-in-cell structures in the liver can have profound effects in liver regeneration, inflammation and cancer. This review brings together the latest reports on four types of endocytosis in the liver -efferocytosis, entosis, emperipolesis and enclysis, with a focus on hepatocyte biology. [ABSTRACT FROM AUTHOR]

Like the organism they constitute, the cells also die in different ways. The death can be predetermined, programmed, and cleanly executed, as in the case of apoptosis, or it can be traumatic, inflammatory, and sudden as many types of necrosis exemplify. Nevertheless, there are a number of cell deaths—some of them bearing a resemblance to apoptosis and/or necrosis, and many, distinct from each—that serve a multitude of roles in either supporting or disrupting the homoeostasis. Apoptosis is coordinated by death ligands, caspases, b-cell lymphoma-2 (Bcl-2) family proteins, and their downstream effectors. Events that can lead to apoptosis include mitotic catastrophe and anoikis. Necrosis, although it has been considered an abrupt and uncoordinated cell death, has many molecular events associated with it. There are cell death mechanisms that share some standard features with necrosis. These include methuosis, necroptosis, NETosis, pyronecrosis, and pyroptosis. Autophagy, generally a catabolic pathway that operates to ensure cell survival, can also kill the cell through mechanisms such as autosis. Other cell-death mechanisms include entosis, ferroptosis, lysosome-dependent cell death, and parthanatos. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes mellitus, characterized by abnormalities of myocardial structure and function. Researches on the models of type 1 and type 2 diabetes mellitus as well as the application of genetic engineering technology help in understanding the molecular mechanism of DCM. DCM has multiple hallmarks, including hyperglycemia, insulin resistance, increased free radical production, lipid peroxidation, mitochondrial dysfunction, endothelial dysfunction, and cell death. Essentially, cell death is considered to be the terminal pathway of cardiomyocytes during DCM. Morphologically, cell death can be classified into four different forms: apoptosis, autophagy, necrosis, and entosis. Apoptosis, as type I cell death, is the fastest form of cell death and mainly occurs depending on the caspase proteolytic cascade. Autophagy, as type II cell death, is a degradation process to remove damaged proteins, dysfunctional organelles and commences by the formation of autophagosome. Necrosis is type III cell death, which contains a great diversity of cell death processes, such as necroptosis and pyroptosis. Entosis is type IV cell death, displaying "cell-in-cell" cytological features and requires the engulfing cells to execute. There are also some other types of cell death such as ferroptosis, parthanatos, netotic cell death, lysosomal dependent cell death, alkaliptosis or oxeiptosis, which are possibly involved in DCM. Drugs or compounds targeting the signals involved in cell death have been used in clinics or experiments to treat DCM. This review briefly summarizes the mechanisms and implications of cell death in DCM, which is beneficial to improve the understanding of cell death in DCM and may propose novel and ideal strategies in future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic disease caused by disorders of insulin secretion and utilization. Long-term hyperglycemia, insulin resistance, and disorders of glucose and lipid metabolism cause vascular endothelial cell damage. Endothelial dysfunction is a key feature of diabetic vascular complications such as diabetic nephropathy, retinopathy, neuropathy, and atherosclerosis. Importantly, cell death is thought to be a key factor contributing to vascular endothelial injury. Morphologically, cell death can be divided into three forms: type I apoptosis, type II autophagy, and type III necrosis. According to the difference in function, cell death can be divided into accidental cell death (ACD) and regulated cell death (RCD). RCD is a controlled process involving numerous proteins and precise signaling cascades. Multiple subroutines covered by RCD may be involved in diabetic endothelial dysfunction, including apoptosis, autophagy, necroptosis, pyroptosis, entosis, ferroptosis, ferroautophagy, parthanatos, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, cuproptosis, and PANoptosis. This article briefly reviews the mechanism and significance of cell death associated with diabetic endothelial dysfunction, which will help deepen the understanding of diabetic endothelial cell death and provide new therapeutic ideas. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with high intratumoral heterogeneity. There is a lack of effective therapeutics for PDAC. Entosis, a form of nonapoptotic regulated cell death mediated by cell-in-cell structures (CICs), has been reported in multiple cancers. However, the role of entosis in PDAC progression remains unclear. CICs were evaluated using immunohistochemistry and immunofluorescence staining. The formation of CICs was induced by suspension culture. Through fluorescence-activated cell sorting and single-cell RNA sequencing, entosis-forming cells were collected and their differential gene expression was analyzed. Cell functional assays and mouse models were used to investigate malignant phenotypes. Clinical correlations between entosis and PDAC were established by retrospective analysis. Entosis was associated with an unfavorable prognosis for patients with PDAC and was more prevalent in liver metastases than in primary tumors. The single-cell RNA sequencing results revealed that several oncogenes were up-regulated in entosis-forming cells compared with parental cells. These highly entotic cells demonstrated higher oncogenic characteristics in vitro and in vivo. NET1 , neuroepithelial cell transforming gene 1, is an entosis-related gene that plays a pivotal role in PDAC progression and is correlated with poor outcomes. Entosis is correlated with PDAC progression, especially in liver metastasis. NET1 is a newly validated entosis-related gene and a molecular marker of poor outcomes. PDAC cells generate a highly aggressive subpopulation marked by up-regulated NET1 via entosis, which may drive PDAC progression. [Display omitted] Entosis plays a pivotal role in pancreatic ductal adenocarcinoma progression by generating cancer cells with enhanced malignant behavior. Targeting the entotic processes of pancreatic ductal adenocarcinoma cells may be an optional therapeutic strategy. [ABSTRACT FROM AUTHOR]

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.

Entosis is a mechanism of cell death that involves neighbor cell ingestion. This process occurs in cancers and promotes a form of cell competition, where winner cells engulf and kill losers. Entosis is driven by a mechanical differential that allows softer cells to eliminate stiffer cells. While this process can be induced by matrix detachment, whether other stressors can activate entosis is unknown. Here, we find that entosis is induced in adherent cells by glucose withdrawal. Glucose withdrawal leads to a bimodal distribution of cells based on their deformability, where stiffer cells appear in a manner requiring the energy-sensing AMP-activated protein kinase (AMPK). We show that loser cells with high levels of AMPK activity are eliminated by winners through entosis, which supports winner cell proliferation under nutrient-deprived conditions. Our findings demonstrate that entosis serves as a cellular response to metabolic stress that enables nutrient recovery through neighbor cell ingestion.

In this issue of the Biomedical Journal, we learn about a novel are still largely mysterious mechanism of cell death that is challenging classification systems of cell death pathways and could have important implications for future cancer therapy. We also learn of a promising biomarker to stratify patients into risk groups after stroke. Finally, this issue also includes two studies investigating factors that influence outcome after heart surgery.

The present review summarizes recent experimental evidences about the existence of the non-cell-autonomous death entosis in physiological and pathophysiological contexts, discusses some aspects of this form of cell death, including morphological, biochemical and signaling pathways that distinguish non-cell-autonomous demises from other death modalities and propose to define this new modality of death as type IV programmed cell death.

Entosis is a process that leads to the formation of cell-in-cell structures commonly found in cancers. Here, we identified entosis in hepatocellular carcinoma and the loss of Rnd3 (also known as RhoE) as an efficient inducer of this mechanism. We characterized the different stages and the molecular regulators of entosis induced after Rnd3 silencing. We demonstrated that this process depends on the RhoA/ROCK pathway, but not on E-cadherin. The proteomic profiling of entotic cells allowed us to identify LAMP1 as a protein upregulated by Rnd3 silencing and implicated not only in the degradation final stage of entosis, but also in the full mechanism. Moreover, we found a positive correlation between the presence of entotic cells and the metastatic potential of tumors in human patient samples. Altogether, these data suggest the involvement of entosis in liver tumor progression and highlight a new perspective for entosis analysis in medicine research as a novel therapeutic target., (© 2024. The Author(s).)