|Year : 2016 | Volume
| Issue : 1 | Page : 45-47
Cellular cannibalism: A promising feature to determine cancer prognosis
Sunny Kala, Gurkiran Kaur
Department of Oral Pathology, PDM Dental College and Research Institute, Bahadurgarh, Haryana, India
|Date of Web Publication||16-May-2016|
Department of Oral Pathology, PDM Dental College and Research Institute, Bahadurgarh, Haryana
Source of Support: None, Conflict of Interest: None
Cellular cannibalism is defined as the ability of a cell to engulf another living cell leading eventually to the death of the internalized cell. 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. It is considered as a sort of “feeding” activity aimed at sustaining survival and progression of malignant tumor cells in an unfavorable microenvironment. Cell-in-cell formation promotes tumor progression, by inducing changes in cell ploidy. It is especially valuable as it eventually helps in assessing tumor behavior. 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 behavior.
Keywords: Cannibalism, malignancy, tumor aggressiveness
|How to cite this article:|
Kala S, Kaur G. Cellular cannibalism: A promising feature to determine cancer prognosis. J Oral Res Rev 2016;8:45-7
| Introduction|| |
One of the intriguing aspects of cancer is “cellular cannibalism” that has been considered as an indicator of the adaptive mechanism of the malignant cells to survive. Cannibalism is recognized as a phenomenon commonly used by all organisms, even at the single-cell level, as a survival option. It is not clear whether cells that can feed through other cells are present in the normal human body, but cannibal cells were identified in malignant tumors up to a century ago. More recently, cells with cannibalistic behavior have been detected in tumors of different histology, and their presence has been related to a poor prognosis and aggressive nature.
| Mechanism|| |
The word cannibalism is derived from cannibals which is the Spanish name for the Carib people formerly well known for practicing cannibalism-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 the death of the internalized cell. The phenomenon of cell cannibalism has been observed in several tumors such as lung carcinoma, renal carcinoma, bladder carcinoma, breast carcinoma, endometrial stromal sarcoma, gastric adenocarcinomas, malignant melanoma, and lymphomas. Selected tumor cells behave as lower microorganisms, such as amoebae and bacillus subtilis, which use their eating to feed, whereas professional phagocytes in multicellular animals use their eating to forage the body from necrotic material and debris and to initiate the immune response.
Cannibalism was first described by Leyden in 1904, who used the term “bird's-eye cells” or “signet-ring cells” based on the light microscopic appearance of the cells. The ingested cell is in a vacuole that pushes the nucleus of the cannibalistic cell to the periphery. The role of this process is still not fully understood. Various other terms are also used in literature such as complex cannibalism, pseudo-cannibalism, and xeno-cannibalism. Complex cannibalism is engulfment of more than one cell by the cannibalistic cell. Pseudo cannibalism is the apparent appearance of cannibalism. Here, the smaller cell lies in a depression of the cytoplasm of the larger cell indicating that the two cells have grown in a very narrow space and are crowded against each other. Xeno cannibalism is used for malignant cells engulfing immune cells or cells other than sibling malignant cells, but many authors do not differentiate between cannibalism and xeno-cannibalism and use the term cancer cannibalism or cellular cannibalism for both these phenomenon. This is supported by the idea that the cannibalistic cell does not recognize the different types of adjacent cells but is in an aggressive mode engulfing any cell adjacent to it.
Other cell in cell phenomenon also exists and of these immune cells are the most frequent cells, whose engulfment into other cells is termed as emperipolesis. Another current under discussion cell in cell death pathway is entosis. This is similar to cannibalism and occurs between two homotypic cells and involves tumor cells engulfing tumor cells. In this process, the live tumor cell invades intact into adjacent cell of the same type. Under starvation condition effector cells perform entosis and is similar to autophagy for survival. Hence, it is a unique type of cell in cell, nonautophagosome dependent lysosomal death pathway.
The reason due to which tumor cells end up harboring other living cells remain elusive and the sparse evidence acquired, thus far, has led researchers to propose different hypotheses. Some workers believe that the cannibalistic cells engulf other cells for nutrition as in the study by Sarode and Sarode. They noted that the cannibalistic cell occurs independently with separation from the stroma and other tumor cells. Furthermore, the stroma showed reduced blood vessels and areas of degeneration which could imply reduce source of nutrition to the tumor mass. Whereas others think it is a mechanism of cancer cells to evade the immune mechanism and reach distant sites in the body to form a new colony of cancer cells-metastasis. The latter is supported by the fact that cannibalism is found to be directly related to the aggressiveness of the neoplasm. Certain other workers suggest that cannibalism may be a feature of malignant cells trying to control the tumor growth.
The mechanism underlying the process of cannibalism is not fully understood. Depending on the character of both the host and internalized cells, which cell initiates the process and the molecular players involved may vary. Although there is no final agreement on the mechanism of cell engulfment, a number of important players, like elements of cytoskeleton regulation and cell-cell junctions such as actin, myosin II, cadherins and Rho signaling have been noted. Numerous studies have revealed that cannibalistic cells use caveolin-1, ezrin and actin to consume the cells in contact with its outer membrane. In all cases, the internalized cells are taken up into a vacuole which is surrounded by host plasma membrane and it is so large that it squishes the host's nucleus into a crescent shape along the cell membrane. A cannibalistic vacuole forms which most likely fuses with lysosomes to form caveosomes rich in cathepsin-B., The nuclear shape of the interiorized cell remains as it is although it has a fading oval nucleus. During the course, the interiorized cell is completely engulfed and it dies. The death of the interiorized cell is probably due to lack of nutrition rather than due to lysosomal enzymes, as ultrastructural studies have shown that lysosomal structures are sparsely present in cannibalistic cells compared to the interiorized cell. Cannibal cells remain alive in acidic medium, supporting the concept that the microenvironment has an important role in the selection of malignant cell clones which could survive in the unfavorable conditions established by the low blood supply (i.e., hypoxia and acidity). ATPase mediated acidification in the caveosomes keeps cathepsin-B in the active state to perform the degradation., 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. Various studies have shown that cannibalism is one of the favored survival mechanism of malignant cells under starvation.
| Future Prospects|| |
The phenomenon of cannibalism provides a promising entity to determine the aggressiveness and hence the prognosis of a tumor. Various studies have shown supporting results. 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. Indeed, cannibalistic activity has been shown to be significantly associated with increased metastatic melanoma cell survival, particularly under starvation conditions. Sarode and Sarode  found that the poorly differentiated oral squamous cell carcinoma (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 behavior in OSCC. Furthermore in a study on central giant cell granuloma (CGCG) and peripheral giant cell granulomas, they found in aggressive CGCG, mean cannibalistic giant cell frequency was significantly higher than nonaggressive type. Similarly, recurrent cases showed significantly higher mean cannibalistic cell frequency than nonrecurrent cases.
More studies with larger sample size are needed to validate these findings, but the current data suggest that cannibalism in a lesion can be used to determine its aggressiveness.
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Conflicts of interest
There are no conflicts of interest.
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