Centre de recherche en organogénèse expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec Research Center, Quebec, Canada.
Urology Division, Department of Surgery, Laval University, Quebec, Canada.
Mol Cancer Res. 2018 Jul;16(7):1196-1204. doi: 10.1158/1541-7786.MCR-17-0784. Epub 2018 Apr 10.
A particularly important tumor microenvironment relationship exists between cancer cells and surrounding stromal cells. Fibroblasts, in response to cancer cells, become activated and exhibit myofibroblastic characteristics that favor invasive growth and metastasis. However, the mechanism by which cancer cells promote activation of healthy fibroblasts into cancer-associated fibroblasts (CAF) is still not well understood. Exosomes are nanometer-sized vesicles that shuttle proteins and nucleic acids between cells to establish intercellular communication. Here, bladder cancer-derived exosomes were investigated to determine their role in the activation of healthy primary vesical fibroblasts. Exosomes released by bladder cancer cells are internalized by fibroblasts and promoted the proliferation and expression of CAF markers. In addition, cancer cell-derived exosomes contain TGFβ and in exosome-induced CAFs SMAD-dependent signaling is activated. Furthermore, TGFβ inhibitors attenuated CAF marker expression in healthy fibroblasts. Therefore, these data demonstrate that bladder cancer cells trigger the differentiation of fibroblasts to CAFs by exosomes-mediated TGFβ transfer and SMAD pathway activation. Finally, exosomal TGFβ localized inside the vesicle and contributes 53.4% to 86.3% of the total TGFβ present in the cancer cell supernatant. This study highlights a new function for bladder cancer exosomes as novel modulators of stromal cell differentiation. This study identifies exosomal TGFβ as new molecular mechanism involved in cancer-associated fibroblast activation. .
一种特别重要的肿瘤微环境关系存在于癌细胞和周围基质细胞之间。成纤维细胞对癌细胞作出反应，被激活并表现出有利于浸润生长和转移的肌成纤维细胞特征。然而，癌细胞促进健康成纤维细胞转化为癌相关成纤维细胞（CAF）的机制仍未得到很好的理解。外泌体是在细胞间穿梭蛋白质和核酸以建立细胞间通讯的纳米大小的囊泡。在这里，研究了膀胱癌衍生的外泌体，以确定它们在激活健康原代膀胱成纤维细胞中的作用。膀胱癌细胞释放的外泌体被成纤维细胞内化，并促进 CAF 标志物的增殖和表达。此外，癌细胞来源的外泌体含有 TGFβ，并且在外泌体诱导的 CAF 中 SMAD 依赖性信号被激活。此外，TGFβ抑制剂减弱了健康成纤维细胞中 CAF 标志物的表达。因此，这些数据表明，膀胱癌细胞通过外泌体介导的 TGFβ转移和 SMAD 途径激活触发成纤维细胞向 CAF 的分化。最后，外泌体 TGFβ定位于囊泡内，并且在癌细胞上清液中存在的总 TGFβ中占 53.4%至 86.3%。本研究强调了膀胱癌外泌体作为新型基质细胞分化调节剂的新功能。本研究确定了外泌体 TGFβ作为参与癌相关成纤维细胞激活的新分子机制。
