Prognostic Value of Homotypic Cell Internalization by Nonprofessional Phagocytic Cancer Cells

Abstract

Background. In this study, we investigated the prognostic role of homotypic tumor cell cannibalism in different cancer types. Methods. The phenomenon of one cell being internalized into another, which we refer to as “cell-in-cell event,” was assessed in 416 cases from five head and neck cancer cohorts, as well as one anal and one rectal cancer cohort. The samples were processed into tissue microarrays and immunohistochemically stained for E-cadherin and cleaved caspase-3 to visualize cell membranes and apoptotic cell death. Results. Cell-in-cell events were found in all of the cohorts. The frequency ranged from 0.7 to 17.3 cell-in-cell events per mm2. Hardly any apoptotic cells were found within the cell-in-cell structures, although apoptotic cell rates were about 1.6 to two times as high as cell-in-cell rates of the same tissue sample. High numbers of cell-in-cell events showed adverse effects on patients' survival in the head and neck and in the rectal cancer cohorts. In multivariate analysis, high frequency was an adverse prognostic factor for overall survival in patients with head and neck cancer (p = 0.008). Conclusion. Cell-in-cell events were found to predict patient outcomes in various types of cancer better than apoptosis and proliferation and might therefore be used to guide treatment strategies.

Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas

“…Concomitantly, differing assumptions on this issue have been provided and Huang et al point out that CIC profiles may vary from tumor to tumor which may indicate different malignant stages and/or inflammatory conditions [12, 14]. On the ground of our previous findings we can support the proposition that each tumor type may harbor its own unique CIC pattern [10, 12]. …”

“…In our previous study 99.5% of CICs were negative for cleaved caspase-3 going in line with the present finding that apoptotic cells are very infrequently involved in the formation of CICs. There was also no correlation between these events, indicating that high numbers of apoptotic cells do not promote CIC formation [10]. Additionally we demonstrated in our previous studies that phagocytosis by nonprofessional phagocytes including primary fibroblasts, pancreatic adenocarcinoma, glioblastoma and head and neck cancer cells serves as a mechanism to remove primary necrotic cells [11].…”

“…These mechanisms all have in common that a living cell is taken up by another non-professional phagocytizing cell and can be broadly characterized as heterotypic or homotypic [8]. Although it is shown that an engulfed cell is able to remain in the host cell, evade the host cell or undertake cell division, phagocytosis most likely leads to cell death of the incorporated cell and a subsequent decomposition [9, 10]. Although the CIC phenomenon has recently gained more and more attention, so far exact details of its characteristics and mechanisms remain unclear.…”

Mechanisms and consequences of entosis

“…Therefore entosis could promote tumor progression by participating in multiple pro-tumor activities, by supporting the survival and proliferation of cells that also propagate gross aneuploidy (Figure 2B). The reported correlations between homotypic cell-in-cell structures like those formed by entosis and high tumor grade (Abodief et al 2006; Krajcovic et al 2011) as well as poor patient outcome (Schwegler et al 2015) may indeed support the idea that this cell behavior promotes tumor progression.…”

“…Cell structures resembling those formed by entosis have been documented in a variety of human cancers, including breast, colon, liver, and pancreatic carcinoma, and others (Huang et al 2015a; Overholtzer et al 2007; Schwegler et al 2015). Similar to entotic structures in culture, engulfing cell structures from clinical breast tumor samples exhibit localization of the cell-cell adhesion protein β-catenin at the engulfing cell interface, and myosin light chain, phosphorylated at the ROCK I/II site (pMLC-S19), at the cortex of internalizing cells (Overholtzer et al 2007; Sun et al 2014a).…”