Laboratory of Molecular Pathology, Department of Health Sciences, Università Del Piemonte Orientale "A. Avogadro", Novara, 28100, Italy; Department of Biochemistry, Faculty of Medicine, Cholangiocarcinoma Research Institution, Khon Kaen University, Khon Kaen, 40002, Thailand.
Laboratory of Molecular Pathology, Department of Health Sciences, Università Del Piemonte Orientale "A. Avogadro", Novara, 28100, Italy.
Cancer Lett. 2018 Aug 28;430:160-171. doi: 10.1016/j.canlet.2018.05.031. Epub 2018 May 23.
Cholangiocarcinoma (CCA), the cancer arising from the epithelial cells of bile ducts, is a prototype of inflammatory-driven cancer. Cytokines released by cancer associated fibroblasts (CAFs) play a pivotal role in CCA progression, driving the epigenetic Epithelial-to-Mesenchymal transition and the growth and metastasization of CCA cells. Consistently, the conditioned medium from CCA-derived CAFs further stimulated the secretion of IL-6, and to a lesser extent of IL-8, by CCA cells. CCA has a poor prognosis, because of late diagnosis and of high resistance to radio- and chemo-therapy of CCA cells. Targeting the CAFs and their secretion could be an alternative option. We found that while IL-6 indeed promoted the cell migration of invasive CCA cells, the nutraceutical Resveratrol strongly counteracted this effect both in CCA cells and in immortalized cholangiocytes. More importantly, here we show that Resveratrol has the potential to abrogate the secretion of IL-6 by CAFs. While the conditioned medium from CAFs strongly induced IL-6 mediated motility of CCA cells, the conditioned medium from CAFs pre-treated with Resveratrol completely halted cancer cell motility and reverted the N-to E-cadherin switch in migrating cells. This effect was associated with stimulation of autophagy in the cancer cells. This is the first demonstration that CAFs secretory products directly affect the regulation of autophagy and consequently the behavior of CCA cells, and that a nutraceutical may revert the malignant phenotype of cancer cells by acting on CAFs metabolism and secretion.
胆管癌（CCA）是一种起源于胆管上皮细胞的癌症，是炎症驱动型癌症的典型代表。癌症相关成纤维细胞（CAFs）释放的细胞因子在 CCA 的进展中起着关键作用，驱动着 CCA 细胞的表观遗传上皮-间充质转化以及生长和转移。一致地，CCA 衍生的 CAFs 的条件培养基进一步刺激了 CCA 细胞中 IL-6 的分泌，并且在较小程度上刺激了 IL-8 的分泌。CCA 的预后较差，因为其诊断较晚，以及 CCA 细胞对放射和化学疗法的高度耐药性。针对 CAFs 及其分泌可能是一种替代选择。我们发现，虽然 IL-6 确实促进了侵袭性 CCA 细胞的迁移，但营养保健品白藜芦醇在 CCA 细胞和永生化胆管细胞中强烈抑制了这种作用。更重要的是，我们在这里表明白藜芦醇有可能消除 CAFs 的 IL-6 分泌。虽然 CAFs 的条件培养基强烈诱导了 IL-6 介导的 CCA 细胞迁移，但用白藜芦醇预处理的 CAFs 的条件培养基完全阻止了癌细胞的迁移，并使迁移细胞中的 N 到 E-钙粘蛋白转换恢复正常。这种作用与癌细胞自噬的刺激有关。这是第一个证明 CAFs 分泌产物直接影响自噬的调节，从而影响 CCA 细胞行为的证明，并且营养保健品可以通过作用于 CAFs 的代谢和分泌来逆转癌细胞的恶性表型。
