Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells.
Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells.
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DOI：
10.1038/onc.2016.353
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发表时间：
2017-03-30
期刊：
影响因子：
8
通讯作者：
Hill R
中科院分区：
文献类型：
--
作者：
Richards KE;Zeleniak AE;Fishel ML;Wu J;Littlepage LE;Hill R
癌相关成纤维细胞（CAF）构成胰腺腺癌（PDAC）的大部分肿瘤体积。目前根除这些肿瘤的努力主要集中在靶向快速生长的癌上皮细胞的增殖。我们知道，这在很大程度上是无效的，大多数肿瘤在暴露于化疗后产生耐药性。尽管长期以来人们认识到CAF在PDAC中的重要性，但化疗对CAF的影响以及它们如何导致邻近癌细胞的耐药性尚未得到很好的表征。在这里，我们表明暴露于化疗的CAFs在调节癌细胞的存活和增殖中起着积极的作用。我们发现CAF对PDAC的化疗标准吉西他滨具有内在耐药性。此外，暴露于吉西他滨的CAF显著增加了称为外泌体的细胞外囊泡的释放。这些外泌体增加了受体上皮细胞中的化学抗性诱导因子Snail，并促进增殖和耐药性。最后，用外来体释放抑制剂GW 4869处理暴露于吉西他滨的CAF显著降低了共培养的上皮细胞的存活率，表明CAF外来体在化疗药物抗性中的重要作用。总的来说，这些发现显示了外泌体抑制剂作为与化疗一起克服PDAC耐药性的治疗选择的潜力。
Cancer associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here we show that CAFs exposed to chemotherapy play an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.