Cannibalism of Live Lymphocytes by Human Metastatic but Not Primary Melanoma Cells

Abstract

The phenomenon of cell cannibalism, which generally refers to the engulfment of cells within other cells, was described in malignant tumors, but its biological significance is still largely unknown. In the present study, we investigated the occurrence, the in vivo relevance, and the underlying mechanisms of cannibalism in human melanoma. As first evidence, we observed that tumor cannibalism was clearly detectable in vivo in metastatic lesions of melanoma and often involved T cells, which could be found in a degraded state within tumor cells. Then, in vitro experiments confirmed that cannibalism of T cells was a property of metastatic melanoma cells but not of primary melanoma cells. In particular, morphologic analyses, including time-lapse cinematography and electron microscopy, revealed a sequence of events, in which metastatic melanoma cells were able to engulf and digest live autologous melanoma-specific CD8 + T cells. Importantly, this cannibalistic activity significantly increased metastatic melanoma cell survival, particularly under starvation condition, supporting the evidence that tumor cells may use the eating of live lymphocytes as a way to ''feed'' in condition of low nutrient supply. The mechanism underlying cannibalism involved a complex framework, including lysosomal protease cathepsin B activity, caveolae formation, and ezrin cytoskeleton integrity and function. In conclusion, our study shows that human metastatic melanoma cells may eat live T cells, which are instead programmed to kill them, suggesting a novel mechanism of tumor immune escape. Moreover, our data suggest that cannibalism may represent a sort of ''feeding'' activity aimed at sustaining survival and progression of malignant tumor cells in an unfavorable microenvironment. (Cancer Res 2006; 66(7): 3629-38)

Pleiotropic function of ezrin in human metastatic melanomas

“…23,24 Our study shows that this function is specifically related to the connection between ezrin and some lysosomal (Lamp-1) and endosomal (Rab 5b) antigens, thus supporting a key role of ezrin in the cannibal machinery. 23 We show ezrin and Lamp-1 interaction in human melanoma through co-immunoprecipitation experiments, further supported by FRET analysis.…”

“…22 Recently, we reported ezrin involvement in a mostly neglected tumor function such as phagocytic activity or cannibalism of metastatic melanoma cells, that is an exclusive property of cells derived from metastatic lesions. 23,24 However, we did not identify the specific ezrin interaction with cannibal vacuoles. Another footprint of malignancy is also represented by the localization on the cell plasma membrane of Lamp-1.…”

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

“…This sensitization could involve the inhibition of the H þ -ATP synthase by resveratrol (48). Similarly to the proton pump inhibitor omeprazole (49), resveratrol could affect the lysosomal function and reduce cell environment acidity, thereby facilitating the drug activity (50). Interestingly, Parolini and colleagues have described that acidity may also change the lipid composition of tumor cell membrane and consequently play an important role in the internalization of exosomes in tumor cells (51).…”

From regulation of dying cell engulfment to development of anti-cancer therapy

“…It has been reported that human metastatic melanoma cells but not primary melanoma cells can engulf living autologous melanoma-specific CD8 þ T cells. 39 The underlying mechanisms of recognition and engulfment implicated in the uptake of live cells are currently unknown, and it will be important to understand in molecular terms how some cancer cells can overcome repelling signals displayed by their live targets.…”