|Year : 2015 | Volume
| Issue : 1 | Page : 14-18
Cellular cannibalism: An insight
Deepti Sharma, George Koshy, Sonal Grover, Shinu Koshy
Department of Oral and Maxillofacial Pathology, Christian Dental College, Ludhiana, Punjab, India
|Date of Web Publication||14-Jan-2015|
Department of Oral Pathology and Microbiology, Christian Dental College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
The phenomenon of cell cannibalism refers to the engulfment of cells within other cells. It is an unusual phenomenon associated with poor prognosis of high-grade cancers. It has been suggested that cannibalism may represent a sort of "feeding" activity aimed at sustaining survival and progression of malignant tumor cells in an unfavorable microenvironment. There is a paucity of literature relevant to cell in cell phenomenon associated with oral cancer. In this review, an attempt has been made to unveil the intricacies of cellular engulfments.
Keywords: Apoptosis, cancer, cannibalism, microenvironment, ploidy
|How to cite this article:|
Sharma D, Koshy G, Grover S, Koshy S. Cellular cannibalism: An insight. CHRISMED J Health Res 2015;2:14-8
| Introduction|| |
Cellular proliferation is a biological process of vital importance to all living organisms and is fundamental to both embryonic and post-embryonic existence. Abnormal cell proliferation appears to be a precursor of cancer development.  Cancer has been a scourge on the human population for many years. Head and neck squamous cell carcinoma is also believed to arise via a multistep process that involves the activation of oncogenes as well as the inactivation of tumor suppressor genes. These genetic changes generate concomitant phenotypic changes in the tumor cells that allow them to continue to survive and expand.  The practice of pathology is currently undergoing significant change, mainly due to advances in the cellular and molecular analysis. However despite therapeutic and diagnostic progress in oncology as a whole during the last decades, the prognosis of oral squamous cell carcinoma (OSCC) remains poor. 
The basic defect of any cellular alteration begins at the molecular level triggering a series of reactions and thereby affecting the entire cell system and consequently its morphology .  One of the intriguing aspects of cancer is "cellular cannibalism" that has been considered as an indicator of adaptive strategy of the malignant cells to survive.  Cannibalism is recognized as a phenomenon commonly used by unicellular and higher organisms, even at single-cell level, as a survival option. It is not clear whether cells, able to feed through other cells, are present in a normal human body, but cannibal cells were identified in malignant tumors up to a century ago. More recently, cells with cannibalistic behaviour have been detected in tumors of different histology, and their presence has been related to a poor prognosis and aggressive nature.  Literature review in relation to this phenomenon involving oral cancer is not vast till date. 
The word cannibalism is derived from cannibals, the Spanish name for the Carib people formerly well known for practicing cannibalism that is the act or practice of humans eating the flesh or internal organs of other human beings. Cellular cannibalism is defined as the ability of a cell to engulf another living cell leading eventually to death of the internalized cell.  This phenomenon is often observed in tumor cells and is a matter of keen interest for the pathologist. It has been considered as an important morphologic feature to distinguish benign from malignant lesions and an emerging indicator of both the anaplastic grade and invasiveness. Cannibalism has even been hypothesized to be related to the metastatic capabilities of malignant cells. This phenomenon of cell cannibalism has been described in several tumors such as lung carcinoma, renal carcinoma, bladder carcinoma, breast carcinoma, endometrial stromal sarcoma, gastric adenocarcinomas, malignant melanoma and lymphomas. ,
Cannibalism was first described by Leyden in 1904, who used the term "bird's-eye cells" or "signet-ring cells." The role of this process is not fully understood.  It may function as a way of eliminating malignant cells or alternatively the ingested cell may serve as a source of nutrients for the proliferating cell that shows this cannibalistic behaviour.  Recently there has been renewed interest by researchers to assess the affect of this phenomenon in relation to prognosis of OSCC and salivary gland pathologies.  However, the studies related to the presence and significance of cannibalism in relation to cytology and histopathology of OSCC and other head and neck malignancies are still limited.
| Mechanism and Molecular Basis of The Phenomenon|| |
The mechanism by which tumor cells end up harboring other living cells remains elusive and the sparse evidence acquired, thus far, has led researchers to propose different hypotheses. Depending on the character of both the host cell and internalized cells, which cell initiates the process and the molecular players involved may vary. However, the exact mechanisms involved and factors controlling cannibalism are not completely resolved. It is believed that cannibalism occurs so that tumor cells can feed on ingested cells and may be related to tumor cell nutritional deficiencies.  Although there is no consensus on the mechanism of cell engulfment, a number of important players, including many elements of cytoskeleton regulation and cell-cell junctions such as actin, myosin II, cadherins and Rho signalling have been identified. Researchers have also found roles for ezrin, a protein that links the plasma membrane with the actin cytoskeleton, and caveolin-1, a main component of invaginations in the plasma membrane called caveolae, which have been proposed to participate in the uptake of bacteria and viruses. ,
In all cases, the internalized cells are taken up into a vacuole surrounded by the host plasma membrane and is so large that it squishes the host's nucleus into a crescent shape along the cell's perimeter - an identifying characteristic of the phenomenon [Figure 1]. The nuclear shape of the interiorized cell remains unchanged although it has a fading oval nucleus. In the course of time, the interiorized cell is completely encircled and dies off. The death of the interiorized cell is apparently due to lack of nutrition rather than due to effect of lysosomal enzymes, as electron microscopy has shown that lysosomal structures are sparsely present in cannibalistic cells compared to the interiorized cell.  The cellular pathways that lead to their demise, however, may be as diverse as the mechanisms by which they are engulfed in the first place.
Cannibal cells remain alive in acidic medium, supporting the concept that the microenvironment has a key role in the selection of malignant cell clones which could survive in the unfavourable conditions established by the low blood supply (i.e. hypoxia and acidity). , Altogether then, it seems that the driving force of the ''cannibalistic vacuole'' is represented by a simple and highly efficient mechanism through which any live or dead material that touches the tumor cell external membrane is immediately endocytosed. A membrane to cytosol framework, including a dynamic link between caveolin-1, ezrin, and actin, seems to have a key role in the formation of the ''cannibalistic vacuole.'' This connection allows the formation of caveolae enriched endosomes called as caveosomes that seem to represent the driving structure of cannibalism. These caveosomes contain simple but highly efficient digestive machinery as represented by an acidic milieu and a potent proteolytic enzyme, such as cathepsin B. In fact, inhibition of the activity of the various factors of tumor cannibalism, including ezrin, caveolae, and cathepsin B, has led to substantial inhibition of cannibalistic activity. ,,
Current concepts and review of the literature
In cytological or histological samples of tumors it is a common finding to detect cells with one or more vacuoles, possibly containing cells under degradation, that push the nucleus to the periphery giving it the shape of a crescent moon.  Once one cell is inside the other, however, the structures formed are nearly indistinguishable, and the internalized cells seem to undergo different fates. Until recently, cannibalism was recognized as a phenomenon seen mainly with tumor cells ingesting other tumor cells. Recent reports have shown tumor cell engulfment of other cells (xeno-cannibalism) such as neutrophils, lymphocytes, and erythrocytes. 
Tumor cell cannibalism of hematopoietic cells (neutrophils, lymphocytes and erythrocytes) has been reported in oral carcinomas, salivary gland malignancies, endometrial tumors and melanoma, implying that cannibal tumor cells do not distinguish or select between the normal cells (including stromal or tumor-infiltrating immune cells) and sibling neoplastic cells. It has also been found that metastatic cells cannibalize their siblings as well as cells from the immune system, which represents a formidable opportunity for metastatic cells to survive in adverse conditions. 
Chandrasoma P hypothesized that this phenomenon could be used as a marker for the metastatic potential of the tumor cells.  Studies have shown that metastatic tumor cells use cannibalism to feed in conditions of low nutrient supply and this property offers them a survival advantage. A study by Lugini et al., showed that melanoma cell lines derived from metastatic lesions exhibited cannibalism, whereas primary tumors did not show this phenomenon. Their data suggested that by feeding on cytotoxic lymphocytes, tumor cells may use cannibalism as tumor immune escape mechanism. Indeed, cannibalistic activity has been shown to be significantly associated with increased metastatic melanoma cell survival, particularly under starvation conditions. 
Sarode et al. aimed their research at identification and quantification of the cannibalistic cells on routine haematoxylin and eosin stained sections of OSCC with clinicopathological correlation. Supporting immunohistochemistry was done to substantiate the cancer cannibalism. They found that the poorly differentiated OSCC reported more number of cannibalistic cells per high power field as compared to moderately differentiated OSCC and it was concluded that cannibalism is easily identifiable and a vital marker of aggressive biological behaviour in OSCC.  Sarode and Sarode in retrospective histopathological analysis of OSCC for identification of neutrophil tumor cell cannibalism (NTCC) and its correlation with clinicopathological parameters concluded that it could predict the biological behaviour and could serve as a useful prognostic marker in future.  This interesting phenomenon has not been previously documented in association with salivary gland tumors however Arya et al. reported NTCC associated with a high-grade, aggressive and metastatic salivary duct carcinoma of the parotid gland by both cytological and histological assessment. 
Any description in the literature of cannibalism in a benign tumor is rare. However, Fernandez-Flores have shown images of cannibalism in a benign condition, namely the localized type of giant cell (GC) tumor of the tendon sheath. It was observed that the internalized cells frequently displayed an apoptotic appearance when stained with hematoxylin-eosin, with the loss of the nucleus and an increase in cytoplasmic density. Their immunohistochemistry analysis revealed that the internalized cells as well as the cannibal cells expressed CD68, which is a reflection of their histiocytic nature. However, the surviving internalized cells did not express the apoptotic markers Bax or p53. In contrast, expression of caspase-3 was evident occasionally in the internalized cells substantiating that the internalization induces the apoptotic death of the internalized cell. No immunoexpression of Bcl-2 was found for the internalized cells. 
Sarode and Sarode studied the cannibalistic GCs in central GC granuloma (CGCG) and peripheral GC granuloma (PGCG) and their correlation with the biological behaviour They found that the frequency of occurrence of cannibalistic GCs ranged from 20% to 56%. CGCG showed significantly higher mean cannibalistic GC frequency than PGCG. In aggressive CGCG, mean cannibalistic GC frequency was significantly higher than non-aggressive type. Similarly, recurrent cases showed significantly higher mean cannibalistic cell frequency than non-recurrent cases. 
Cannibalism has been considered as a completely different entity than phagocytosis, autophagy, entosis and emeriopoliosis [Table 1].  It is considered as a sort of "feeding" activity aimed at sustaining survival and progression of malignant tumor cells in an unfavourable microenvironment. Selected tumor cells behave as unicellular microorganisms, such as amoebae and bacillus subtilis, which use their eating to feed, whereas professional phagocytes in higher animals use their eating to scavenge the body from necrotic material and debris and to initiate the immune response. Recently, some authors support the concept that cell-in-cell formation promote tumor progression, by inducing changes in cell ploidy. It is especially valuable as it eventually helps in assessing tumor behaviour. 
| Conclusion|| |
There is a paucity of literature regarding tumor cell cannibalism in oral cancer. More research work is required to thoroughly comprehend this phenomenon. The depth of basic physiology and molecular biology needs to be revealed and substantiated with sufficient data to ascertain its role in routine cytological, histopathological assessment and prognosis of oral cancer. It is felt that future studies on various aspects of cannibalism such as histological, biochemical and molecular aspects in OSCC will reveal some interesting facts that would lead to some useful conclusions. This could help in the diagnosis, prognosis and treatment planning of OSCC.
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