Extracellular Vesicles Shedding Promotes Melanoma Growth in Response to Chemotherapy

Luciana Nogueira De Sousa Andrade,Mariana Mari Ikoma Sakamoto,Fátima Solange Pasini,Andréia Hanada Otake,Felipe Ilelis Da Silva,Miyuki Uno,Silvia Guedes Braga Cardim,Tatiane Katsue Furuya,Roger Chammas

doi:10.1038/s41598-019-50848-z

Luciana Nogueira De Sousa Andrade, Mariana Mari Ikoma Sakamoto + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-50848-z

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Abstract

Extracellular vesicles (EVs) are emerging as key players in intercellular communication. EVs can transfer biological macromolecules to recipient cells, modulating various physiological and pathological processes. It has been shown that tumor cells secrete large amounts of EVs that can be taken up by malignant and stromal cells, dictating tumor progression. In this study, we investigated whether EVs secreted by melanoma cells in response to chemotherapy modulate tumor response to alkylating drugs. Our findings showed that human and murine melanoma cells secrete more EVs after treatment with temozolomide and cisplatin. We observed that EVs shed by melanoma cells after temozolomide treatment modify macrophage phenotype by skewing macrophage activation towards the M2 phenotype through upregulation of M2-marker genes. Moreover, these EVs were able to favor melanoma re-growth in vivo, which was accompanied by an increase in Arginase 1 and IL10 gene expression levels by stromal cells and an increase in genes related to DNA repair, cell survival and stemness in tumor cells. Taken together, this study suggests that EVs shed by tumor cells in response to chemotherapy promote tumor repopulation and treatment failure through cellular reprogramming in melanoma cells.

Highlights

Horizontal transfer of biological information by extracellular vesicles (EVs) is an evolutionarily conserved mechanism for cellular communication from prokaryotes to eukaryotes[1]
Since Extracellular vesicles (EVs) may constitute a novel adaptative strategy employed by tumor cells to overcome stressful conditions in tumor microenvironment, we evaluated whether chemotherapy modulates EVs shedding by melanoma cells
Since the release of EVs has been correlated with the acquisition of a chemoresistant phenotype by tumor cells, we evaluated whether EVs secreted by melanoma cells in response to chemotherapy could modulate the drug response in these cells

Summary

Introduction

Horizontal transfer of biological information by extracellular vesicles (EVs) is an evolutionarily conserved mechanism for cellular communication from prokaryotes to eukaryotes[1]. Exosomes secreted by colorectal cancer cells under hypoxia promoted endothelial proliferation and migration in vitro and enhanced tumor growth and angiogenesis in vivo[13]. Tumor cells-derived exosomes activated macrophages to secrete pro-inflammatory cytokines which promoted tumor cell proliferation and migration[19]. We asked whether EVs secreted by melanoma cells under chemotherapy can induce a phenotype reprogramming in tumor cells and in macrophages, affecting tumoral response to alkylating drugs hampering their efficacy. Our results indicate that murine and human melanoma cells secrete higher amount of EVs upon temozolomide (TMZ) and cisplatin (CDDP) treatment These vesicles are taken up by tumor cells; they do not confer growth advantage and/or drug resistance to naïve melanoma cells in vitro, as demonstrated in other tumor types. When admixed with TMZ-treated cells and injected in nude mice, they promote the growth of the remaining viable tumor cells through a nuclear reprogramming, constituting a novel route for tumor repopulation and treatment failure in melanomas

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