Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.
Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.
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人类结肠癌细胞分泌的外泌体会影响邻近转移细胞的粘附：microRNA-210的作用。
DOI：
10.1080/15384047.2016.1219815
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发表时间：
2016-10-02
影响因子：
3.6
通讯作者：
Cinci L
中科院分区：
文献类型：
--
作者：
Bigagli E;Luceri C;Guasti D;Cinci L
癌症分泌的外泌体影响肿瘤微环境并支持癌症生长和转移。miR-210在结直肠癌组织中经常上调，并与转移性疾病相关。我们研究了HCT-8结肠癌细胞是否主动释放外泌体、外泌体miR-210在原发性癌细胞和邻近转移细胞之间的串扰中的作用以及其在调节上皮-间充质转化（EMT）和间充质-上皮转化中的贡献（MET）。培养7天后，一个亚群的活HCT-8细胞脱离单层，并开始在悬浮液中生长，表明抗失巢凋亡和转移潜力。EMT关键蛋白的表达显示，这些细胞是E-cadherin阴性和波形蛋白阳性，进一步证实了其转移表型和获得抗失巢凋亡。在存在粘附生长的HCT-8的情况下，转移细胞继续在悬浮液中生长，而只有当接种在无细胞威尔斯孔中时，才能够再次粘附并形成E-钙粘蛋白阳性和波形蛋白阴性的新集落，这表明MET的发生。与贴壁HCT-8细胞相比，转移细胞对5氟尿嘧啶和FOLFOX样治疗的化疗敏感性显著降低。值得注意的是，接受MET的贴壁新集落对两种化疗策略均不敏感。电子显微镜分析表明，粘附生长的HCT-8实际上分泌外泌体，并且外泌体进而被转移细胞摄取。当将粘附生长的HCT-8分泌的外泌体给予转移性细胞时，MET被显著抑制。与贴壁生长的HCT-8细胞中的细胞内水平相比，miR-210在外泌体中显著上调，并与失巢凋亡抗性和EMT标志物相关。含有miR-210的外泌体可以被认为是EMT促进信号，其保留了局部癌症生长允许环境，并且还引导转移细胞游离到新的传播位点。
Cancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET. The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer-growth permissive milieu and also guide metastatic cells to free, new sites of dissemination.
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