Extracellular Vesicles Shedding Promotes Melanoma Growth in Response to Chemotherapy
Extracellular Vesicles Shedding Promotes Melanoma Growth in Response to Chemotherapy
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DOI：
10.1038/s41598-019-50848-z
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发表时间：
2019-10-09
影响因子：
4.6
通讯作者：
Chammas, Roger
中科院分区：
文献类型：
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作者：
de Sousa Andrade, Luciana Nogueira;Otake, Andreia Hanada;Chammas, Roger
细胞外囊泡（EV）正在成为细胞间通讯的关键参与者。EV可以将生物大分子转移到受体细胞，调节各种生理和病理过程。已经表明，肿瘤细胞分泌大量的EV，其可以被恶性细胞和基质细胞摄取，从而决定肿瘤进展。在这项研究中，我们研究了是否由黑色素瘤细胞分泌的EV在化疗调节肿瘤对烷化剂的反应。我们的研究结果表明，人类和小鼠黑色素瘤细胞分泌更多的EV后，用替莫唑胺和顺铂治疗。我们观察到替莫唑胺治疗后黑色素瘤细胞脱落的EV通过上调M2标记基因使巨噬细胞活化偏向M2表型来改变巨噬细胞表型。此外，这些EV能够促进体内黑色素瘤再生长，这伴随着基质细胞精氨酸酶1和IL 10基因表达水平的增加以及肿瘤细胞中与DNA修复、细胞存活和干细胞相关的基因的增加。总之，这项研究表明，肿瘤细胞对化疗的反应导致EV脱落，通过黑色素瘤细胞中的细胞重编程促进肿瘤再增殖和治疗失败。
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.