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Multiple mechanisms have emerged where the engulfment of whole live cells, leading to the formation of what are called ‘cell-in-cell’ structures, induces cell death. Entosis is one such mechanism that drives cell-in-cell formation during carcinogenesis and development. Curiously, entotic cells participate actively in their own engulfment, by invading into their hosts, and are then killed non-cell-autonomously. Here we review the mechanisms of entosis and entotic cell death and the consequences of entosis on cell populations.

Homotypic entotic figures, which are a form of “cell-in-cell” structures, are considered a potential novel independent prognostic marker in various cancers. Nevertheless, the knowledge concerning the biological role of this phenomenon is still unclear. Since breast cancer cells are remarkably entosis-competent, we aimed to investigate and compare the frequency of entoses in a primary breast tumor and in its lymph node metastasis. Moreover, as there are limited data on defined molecular markers of entosis, we investigated entosis in correlation with classical breast cancer biomarkers used in routine pathomorphological diagnostics (HER2, ER, PR, and Ki67). In the study, a cohort of entosis-positive breast cancer samples paired into primary lesions and lymph node metastases was used. The inclusion criteria were a diagnosis of NOS cancer, lymph node metastases, the presence of entotic figures in the primary lesion, and/or lymph node metastases. In a selected, double-negative, HER2-positive NOS breast cancer case, entoses were characterized by a correlation between an epithelial–mesenchymal transition and proliferation markers. We observed that in the investigated cohort entotic figures were positively correlated with Ki67 and HER2, but not with ER or PR markers. Moreover, for the first time, we identified Ki67-positive mitotic inner entotic cells in clinical carcinoma samples. Our study performed on primary and secondary breast cancer specimens indicated that entotic figures, when examined by routine HE histological staining, present potential diagnostic value, since they correlate with two classical prognostic factors of breast cancer.

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.

Cell-in-cell structures are reported in numerous cancers, and their presence is an indicator for poor prognosis. Mechanistic studies have identified how cancer cells manage to ingest whole neighbouring cells to form such structures, and the consequences of cell-in-cell formation on cancer progression have been elucidated. In this Opinion article, we discuss how two related cell-in-cell processes, cell cannibalism and entosis, are regulated and how these mechanisms promote cancer progression. We propose that cannibalistic activity is a hallmark of cancer that results in part from selection by metabolic stress and serves to feed aggressive cancer cells.

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.

Homotypic entosis is a phenomenon in which one cancer cell invades a neighboring cancer cell and is closed entirely within its entotic vacuole. The fate of entosis can lead to inner cell death or survival. Recent evidence draws attention to entosis as a novel prognostic marker in breast cancer. Nevertheless, little is known about the quantity and quality of the process of entosis in human cancer specimens. Here, for the first time, we analyze the frequency of entotic figures in a case of NOS (Non-Other Specified) breast cancer with regard to location: the primary tumor, regional lymph node, and distant metastasis. For the identification of entotic figures, cells were stained using hematoxylin/eosin and assessed using criteria proposed by Mackay. The majority of entotic figures (65%) were found in the lymph node, 27% were found in the primary tumor, and 8% were found in the far metastasis. In the far metastases, entotic figures demonstrated an altered, atypic morphology. Interestingly, in all locations, entosis did not show any signs of cell death. Moreover, the slides were stained for E-cadherin or Ki67, and we identified proliferating (Ki67-positive) inner and outer entotic cells. Therefore, we propose additional criteria for the identification of pro-survival entotic structures in diagnostic histopathology.

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.

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.

Adaptive strategies used by cells to scavenge and recycle essential nutrients are important for survival in nutrient-depleted environments such as cancer tissues. Autophagy and macropinocytosis are two major mechanisms that promote nutrient recycling and scavenging, which share considerable, yet poorly understood, cross-regulation. Here we review recent findings that connect these starvation response mechanisms and discuss the implications of their crosstalk. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

The epithelial to mesenchymal transition (EMT) has been recently associated with a stem cell phenotype. In breast cancer cell lines and tumours, p53 directly targets the expression of microRNAs that have been shown to inhibit EMT and stem cells regulators. The epithelial–mesenchymal transition (EMT) has recently been linked to stem cell phenotype 1 , 2 . However, the molecular mechanism underlying EMT and regulation of stemness remains elusive. Here, using genomic approaches, we show that tumour suppressor p53 has a role in regulating both EMT and EMT-associated stem cell properties through transcriptional activation of the microRNA miR-200c. p53 transactivates miR-200c through direct binding to the miR-200c promoter. Loss of p53 in mammary epithelial cells leads to decreased expression of miR-200c and activates the EMT programme, accompanied by an increased mammary stem cell population. Re-expressing miR-200c suppresses genes that mediate EMT and stemness properties 3 , 4 and thereby reverts the mesenchymal and stem-cell-like phenotype caused by loss of p53 to a differentiated epithelial cell phenotype. Furthermore, loss of p53 correlates with a decrease in the level of miR-200c, but an increase in the expression of EMT and stemness markers, and development of a high tumour grade in a cohort of breast tumours. This study elucidates a role for p53 in regulating EMT–MET (mesenchymal–epithelial transition) and stemness or differentiation plasticity, and reveals a potential therapeutic implication to suppress EMT-associated cancer stem cells through activation of the p53–miR-200c pathway.