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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 3  |  Page : 631-637

Cell cannibalism in oral cancer: A sign of aggressiveness, de-evolution, and retroversion of multicellularity


1 Department of Oral Pathology and Microbiology, Sardar Patel Post Graduate Institute of Dental and Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Oral Pathology and Microbiology, Saraswati Dental College, Lucknow, Uttar Pradesh, India
3 Department of Community Medicine, Jawahar Lal Nehru Medical College, AMU, Aligarh, Uttar Pradesh, India
4 Department of Pathology, Jawahar Lal Nehru Medical College, Aligarh, Uttar Pradesh, India

Date of Web Publication29-May-2019

Correspondence Address:
Dr. Safia Siddiqui
Department of Oral Pathology and Microbiology, Sardar Patel Post Graduate Institute of Dental and Medical Sciences, Lucknow - 226 025, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_504_17

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 > Abstract 


Background: According to Darwin's theory of evolution, complex creatures evolve from more simplistic ancestors. Dollo's law of irreversibility states that evolution is irreversible. However, cancer cells tend to follow anti-Dollo's law. Unfavorable conditions such as hypoxia, acidic pH and low nutrients cause the cancer cells to switch their lifestyle atavistically in order to survive. They start behaving like a unicellular organism. There is a switch from normal metabolism to Warburg effect and finally cannibalism. Cannibalism is a cell eating cell phenomenon. It is defined as a large cell enclosing a smaller one within its cytoplasm and is known by odd names such as “bird's eye cells” or “signet ring cells.” Smaller tumor cells are found in the cytoplasm of larger tumor cells with crescent-shaped nucleus. Cannibalistic cells (CCs) are a feature of aggressive tumors. These cell types are vulnerable to metastasis.
Aim: The aim of this study is to identify CCs in various histological grades of oral squamous cell carcinoma (OSCC) and to relate them with the pattern of invasion, lymphocytic response (LR), and mitotic figures (Mfs). The purpose of the article is to establish it as a marker of aggressiveness and metastasis and as an evidence of de-evolution and retroversion of multicellularity.
Materials and Methods: Sixty-five histologically confirmed cases of OSCC were studied. Pattern of invasion, LR, number of CCs, and Mfs were recorded on 5 μ hematoxylin and eosin-stained tissue sections. ANOVA and t-test were applied; P < 0.05 was considered statistically significant.
Results: CCs were more in sections with patchy LR, increased Mfs, and grade IV pattern of invasion.
Conclusion: With increase in dedifferentiation, tumor cells start behaving like unicellular organisms with cell eating cell characteristics.

Keywords: Cancer evolution, cancer metabolism, cannibalism, oral squamous cell carcinoma, Warburg effect


How to cite this article:
Siddiqui S, Singh A, Faizi N, Khalid A. Cell cannibalism in oral cancer: A sign of aggressiveness, de-evolution, and retroversion of multicellularity. J Can Res Ther 2019;15:631-7

How to cite this URL:
Siddiqui S, Singh A, Faizi N, Khalid A. Cell cannibalism in oral cancer: A sign of aggressiveness, de-evolution, and retroversion of multicellularity. J Can Res Ther [serial online] 2019 [cited 2019 Dec 13];15:631-7. Available from: http://www.cancerjournal.net/text.asp?2019/15/3/631/237386




 > Introduction Top


Cancer is closely linked to our evolutionary history. Within the complex ecosystem of the human body, cancer cells also evolve. Just like any organism, they face diverse selective pressure to adapt to the tumor environment. There exists a competitive struggle that eliminates the unfit, leaving the well adapted to thrive. Cannibalism is one such strategy that confers the cell a better survival advantage.[1]

Cell cannibalism was first described by Leyden in 1904 as the ability of one cell to phagocytose another cell. It is also defined as a large cell enclosing a smaller one within its cytoplasm and is known by odd names such as “bird's eye cells” or “signet ring cells.”[1] The “bird's eye cells” means smaller tumor cells found in the cytoplasm of larger tumor cells with crescent-shaped nucleus.[2]

The successive steps in the process of cell cannibalism are contact with the cell, engulfment, change in shape of cannibalistic cell (CC) to a semi-lunar shape followed by nuclear disintegration and death of the cell.[3] The internalized cells are taken up into a vacuole surrounded by the host plasma membrane and are so large that it squashes the host's nucleus into a crescent shape along the cell's perimeter – an identifying characteristic of the phenomenon. 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.[4]

Unlike phagocytosis, which involves the engulfment of dead or dying cells, or pathogenic organisms, cannibalism involves the ingestion of live cells, resulting in the unusual appearance of whole cells contained within large vacuoles. Such structures are also known as “cell in cell” (CIC) structures.[4]

Apart from cannibalism, other CIC phenomena are entosis, emperitosis, and emperipolesis.[4],[5] Entosis is characterized by a nonapoptotic cell death of the internalized cell.[6] Emperitosis is killer cell-involved apoptotic CIC death.[4] However, random passage of different types of cells through the cytoplasm of another cell without any important change in either the host or invading cells is known as emperipolesis.[7]

Cell engulfments can occur heterotypically (between cells of different types) or homotypically (between cells of the same type).[8] Until recently, cannibalism was recognized as a phenomenon seen mainly with tumor cells ingesting other tumor cells. Recent reports have shown that tumor cell engulfs other cells as well, such as neutrophils, lymphocytes, and erythrocytes. This is known as xeno-cannibalism.[9],[10] Thus, the term cell cannibalism is described as the ability of tumor cells to cannibalize their siblings' neoplastic cells as well as stromal or tumor-infiltrating immune cells.[1],[5],[9],[11]

Apart from conventional cannibalism, bizarre morphological appearances of cannibalism are also observed, wherein one malignant cell engulfs the other tumor cell and this complex is further engulfed by another cell or one cell engulfs two cells at a time. This phenomenon is termed as “complex cannibalism,” suggestive of a highly aggressive biological behavior in oral squamous cell carcinoma (OSCC).[12]

Lymphocytic response (LR), mitotic activity, and pattern of invasion are used to assess the aggressiveness of a tumor. The aim of this study is to identify CCs in various histological grades of OSCC and to relate it with pattern of invasion, LR, and number of mitotic figures (Mfs) so as to establish it as a marker of aggressiveness and metastasis and evidence of de-evolution and retroversion of multicellularity.


 > Materials and Methods Top


The study was undertaken after approval from the Institutional Scientific and Ethical Committee. From 2011 to 2015, 230 archival cases of OSCC were screened. Sixty-five cases showed evidence of cannibalism and these were taken as the study group. Demographic data of these patients obtained from the records are shown in [Table 1].
Table 1: Patient and disease characteristics with mean cannibalistic cell count

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The study group was divided into four groups as follows:

  • Group 1 – Well-differentiated OSCC (4 cases)
  • Group 2 – Moderately differentiated OSCC (36 cases)
  • Group 3 – Poorly differentiated OSCC (23 cases)
  • Group 4 – Undifferentiated oral carcinoma (epithelial origin confirmed by immunohistochemistry) (two cases of sarcomatoid carcinoma).


Hematoxylin and eosin (H and E)-stained tissue sections at 5 μ were obtained. Worst pattern of invasion (WPOI), LR and Mfs were evaluated according to the criteria shown in [Table 2] and graded accordingly.[13],[14] If two or more grades were seen within the same section, the highest grade, even if focal, is considered the final score. For identification of Mfs, following criteria were applied.[15]
Table 2: Definition of worst pattern of invasion, lymphocytic response, and mitotic activity

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  1. The nuclear membrane must be absent, so cells have passed the prophase
  2. Clear hairy extension of nuclear material (condensed chromosomes) must be present, either clotted (beginning metaphase) in a plane (metaphase/anaphase) or in separate clots (telophase). Regular extension with an empty clear zone favors nonmitosis
  3. Two parallel clearly separate chromosome clots are to be counted as if separate mitosis.


Mfs were counted under a light microscope in 10 random high power fields (Hpfs) using ×10 ocular and ×40 objective.[16]

Three criteria were used to define homotypic CCs: total encirclement of the inner cell by the host cell membrane, a semilunar host cell nucleus, and a round shape of the inner cell.[17] Sections were observed at ×40 objective under light microscope (Olympus BX 51) at 3 different Hpfs, which showed maximum density of such phenomenon. One Hpf is defined by ×10 eyepiece and ×40 objective. The average of three different fields was calculated and expressed as number of CC/Hpf.[18] Cases showing cannibalism of neutrophils, lymphocytes, and red blood cells (RBCs) were also considered if they fulfilled the following criteria: both partial and complete encirclement of the immune cell by the host cell membrane and a semilunar host cell nucleus. Quantification of the immune cells was done by selecting four hot spots showing maximum density of this phenomenon.[19] Cases showing occasionally isolated xeno-cannibalism were excluded from the study.

The four parameters were evaluated independently by two of the authors, and in cases of disagreement, samples were reevaluated in a joint session.


 > Results Top


In the present study group, the mean age of the cases was 66.01 ± 12.28 years, and 70% of the cases were males. The most prevalent habit was that of tobacco chewing (43.07% cases), and the most common site was tongue (27.9%). Most of the patients were in stage IV (72.3%) of the disease, and maximum number of cases (63.3%) had moderately differentiated OSCC. In the study group, the mean CC count ranged from 1 to 10, with a mean of 3.375 ± 1.219 (95% confidence interval - 3.073–3.677). Mean CC count was found to be independent of age and gender of the subjects (P > 0.05).

Total encirclement of the inner tumor cell by the host cell membrane, a semilunar host cell nucleus, and a round shape of the tumor cell was seen [Figure 1]. The internalized cell showed different stages of degeneration. Mitosis in various stages was seen in the section [Figure 2]. Neutrophils could be identified both within the malignant epithelial cells and in the stroma adjacent to the tumor cells. In few sections, isolated CCs were seen engulfing neutrophils [Figure 3]. Since these were isolated CCs, they were excluded from the study. Complex cannibalism was also observed, one malignant cell was seen engulfing another cell, and this complex was engulfed by another cell [Figure 4].
Figure 1: Histopathological image showing cannibalistic cell (green arrow) in a tissue section of well-differentiated squamous cell carcinoma (H and E, ×1000). The host cell nucleus is semilunar in shape, and the engulfed cell is totally within the host cell membrane

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Figure 2: Histopathological image showing cannibalistic cell (green arrows) in a tissue section of poorly differentiated oral squamous cell carcinoma. Mitotic figure in metaphase (yellow arrow) is seen. The section shows grade 3 worst pattern of invasion and grade 3 lymphocytic response (H and E, ×400)

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Figure 3: Histopathological image of a tissue section showing heterotypic cannibalism. Neutrophil (green arrow) is seen within the vacuole of a cannibalistic epithelial cell (H and E, ×400)

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Figure 4: Histopathological image of a tissue section showing complex cannibalism (green arrow) where one malignant cell is engulfing another cell and this complex is engulfed by another cell (H and E, ×400)

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None of the cases in the study group belonged to stage 1. Mean CC count was maximum in stage IV. On comparing the mean CC count of the three groups, ANOVA revealed statistically significantly result (F = 4.85, df = 2, P = 0.011) as shown in [Table 1].

Mean CC count was found to be maximum in undifferentiated carcinoma followed by poorly differentiated OSCC and minimum in well-differentiated OSCC as shown in [Table 1] and [Figure 1], [Figure 5] and [Figure 6]. On comparing the mean CC count of the four groups, ANOVA revealed significantly different levels among the groups (F = 49.691, df = 3, P < 0.001).
Figure 5: Histopathological image of a tissue section of well-differentiated oral squamous cell carcinoma showing cannibalistic cell (green arrow). The section also shows grade 3 worst pattern of invasion and grade 1 lymphocytic response (H and E, ×400)

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Figure 6: Histopathological image showing cannibalistic cells (green arrows), mitotic figures in anaphase and metaphase (yellow arrows), grade 3 worst pattern of invasion, and grade 2 lymphocytic response in section of moderately differentiated oral squamous cell carcinoma (H and E, ×400)

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In the study group, maximum number of cases showed grade 4 WOPI [Figure 6]. The mean CC count was found to be highest with grade 5. On comparing the mean CC count of the five groups, ANOVA revealed significantly different levels among the groups (F = 19.424, df = 3, P < 0.001) as shown in [Table 3].
Table 3: Worst pattern of invasion, lymphocytic response, mean mitotic figures, and mean cannibalistic cells

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Maximum cases exhibited Grade 2 LR as shown in [Table 3]. Mean CCs were also found to be higher in patients with Grade 2 LR [Figure 2]. Unpaired t-test revealed this to be statistically significant (t = 3.4465, df = 63, P = 0.001).

Mean Mfs count ranged from 0 to 17. More Mfs corresponded with more number of CC [Figure 6]. ANOVA revealed significantly different levels among the groups (F = 8.740, df = 2, P < 0.001) as shown in [Table 3].


 > Discussion Top


Tumor cell cannibalism has been reported in lung, gallbladder, hepatobiliary, and pancreatic carcinomas.[20],[21] It has also been reported in gastrointestinal and female genital tract malignancies.[9],[22] CCs have been observed in malignant melanoma and infiltrative ductal carcinoma of the breast, salivary gland carcinomas, and high-grade transitional cell carcinoma of the bladder.[23],[24],[25],[26],[27] Among sarcomas, it is seen in endometrial stromal sarcomas and lymphomas.[21],[25],[26] Cannibalism has also been reported in OSCC.[28],[29] CCs correlated well with aggressiveness, degree of anaplasia, invasiveness, and metastatic potential.[30],[31]

In our study, we found CCs in OSCC patients. This was in accordance with another study in which CD 68-positive cells indicative of CCs were present in the OSCC group.[29] The presence and increased number of CCs have been related to poor prognosis.[10],[17],[28] The phenomenon of complex cannibalism is suggestive of a highly aggressive biological behavior in OSCC. In a case series, it has been seen in only two cases, both of which were in advanced stage and were poorly differentiated OSCC.[12]

We found that maximum number of CCs were present in stage IV and in undifferentiated carcinomas and poorly differentiated carcinomas. Similar results were obtained in another study on OSCC where more CCs were seen in poorly differentiated carcinoma.[28] Mean cannibalistic giant cells were significantly higher in aggressive central giant cell granuloma as compared to the nonaggressive type, suggesting that increased number of CCs is a feature of aggressive tumors.[31] In another study on 151 patients of gastric micropapillary carcinoma, it was found that tumor cell cannibalism is usually found in aggressive tumors with anaplastic morphology.[6] All these findings suggest that cannibalism is a marker of aggressive biological behavior.[28]

A probable explanation for increased CCs in dedifferentiated carcinomas is that as cancer evolves and de-differentiates, tumor cells switch their lifestyle atavistically to survive the unfavorable conditions and start behaving like a unicellular organism and developing cell eating cell behavior.[32] The change in metabolism of the tumor is responsible for this phenomenon. Conditions such as hypoxia, acidic pH and low nutrients due to chaotic vasculature causes a metabolic transformation in the tumor; there is a physiological switch from normal metabolism to Warburg effect and finally cannibalism.[33]

Hypoxia favors a shift of glucose metabolism to less efficient glycolytic pathways even in conditions of adequate oxygen supply (aerobic glycolysis or “Warburg effect”).[34],[35],[36],[37] Tumors produce lactic acid at a marked rate.[36] Acidic conditions increase the phenomenon of cannibalism.[3] Any live or dead material that touches the tumor cell external membrane is immediately endocytosed by the CC.[10]

Caveolin-1, ezrin, and actin have a key role in the formation of the “cannibalistic vacuole.” This vacuole contains a potent proteolytic enzyme cathepsin B and has an acidic milieu, thus presenting highly efficient digestive machinery. Role of actin, myosin II, cadherins, and Rho signaling has also been identified.[5],[10],[38],[39]

Histological risk assessment evaluating WPOI and LR has previously been shown to be of prognostic significance in squamous cell carcinomas of the head and neck. Studies indicate that evaluation of the intensity of the inflammatory infiltrate at the tumor interface in SCC could provide information of potential importance for choice of treatment and prognosis.[40]

CCs were more in higher grades of WOPI, suggesting that as the tumor cells lose their physiological characteristics such as differentiation and cohesion, they acquire new traits such as cell eating cell behavior which help them in eliminating other less-advantaged cells.[41],[42]

Regarding LR, both the presence and the state of activation of immunological cells play a role in tumor progression.[43] In a Th-2 polarized microenvironment, there is exacerbation of local immune responses and suppression of tumor occurs, whereas in a Th-1 polarized microenvironment, suppression of immune response and progression of tumor occur.[44] Since CCs were more when the LR was less, we hypothesize that when CCs are more, the microenvironment is Th-1 polarized and tumor progression is favored. Further studies are needed to validate it.

More number of Mfs indicates more cell division and hence increased tumor burden. Higher number of CCs corresponds with more Mfs, suggesting that as the tumor load increases, there is a scarcity of nutrients. To survive, tumor cells start eating other cells. This is a survival strategy independent of vasculature.[10],[24] 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.[45]

Regarding the biological significance of cannibalism, we need to revisit evolution again. As the organisms evolved from unicellular to pluricellular, it was seen that each cell, instead of behaving independently, submits itself and works under the guidance of a tight physiological control. The tumor cell undergoes a complete reversal of this feature. As cancer evolves, individual cells behave more like a unicellular organism focused on their own survival.[46]

CCs have a survival advantage over other tumor cells. First, by eating other cells, it can survive on its own independent of the microvasculature.[10],[24] Second, CCs can produce nongenetic polyploidy.[47] Cannibalism-mediated chromosomal instability and aneuploidy could be one of the reasons for aggressive behavior of carcinoma, but further studies are needed to verify these hypotheses.[6],[48],[49],[50] Third, by feeding on cytotoxic lymphocytes, tumor cells may use cannibalism as tumor immune escape mechanism.[45]


 > Conclusion Top


Tumor cell cannibalism is believed to be an indicator of high-grade aggressive cancers with increased metastatic potential. It is valuable in assessing tumor behavior.[32] Demonstration of an increased number of CCs may also be a parameter in grading OSCC. Actions aimed at inhibiting tumor cannibalism may have utility as a pharmacological target in the management of metastatic disease.[32] Inhibition of tumor acidity through specific agents may represent a further therapeutic approach against cannibalistic activity.[47]

Cancer cells follow anti-Dollo's law; cannibalistic behavior of tumor cells is reminiscent of bacteria. An analogy between the evolution of drug resistance in bacterial communities and malignant tissue could be of help in developing new treatment modalities in drug-resistant cancers.[51] An evolutionary analogy can open up vistas in the treatment of this dreadful disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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