Background: The interaction between cancer cells and cancer-associated fibroblasts (CAFs) is a key determinant of the rapid progression, high invasiveness, and chemoresistance of aggressive desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC). Tumor cells are known to reprogram fibroblasts into CAFs by secreting transforming growth factor beta (TGF-β), amongst other cytokines. In turn, CAFs produce soluble factors that promote tumor-cell invasiveness and chemoresistance, including TGF-β itself, which has a major role in myofibroblastic CAFs. Such a high level of complexity has hampered progress toward a clear view of the TGFβ signaling loop between stromal fibroblasts and PDAC cells. Methods: Here, we tackled this issue by using co-culture settings that allow paracrine signaling alone (transwell systems) or paracrine and contact-mediated signaling (3D spheroids). Results: We found that TGF-β is critically involved in the activation of normal human fibroblasts into alpha-smooth muscle actin (α-SMA)-positive CAFs. The TGF-β released by CAFs accounted for the enhanced proliferation and resistance to gemcitabine of PDAC cells. This was accompanied by a partial epithelial-to-mesenchymal transition in PDAC cells, with no increase in their migratory abilities. Nevertheless, 3D heterospheroids comprising PDAC cells and fibroblasts allowed monitoring the pro-invasive effects of CAFs on cancer cells, possibly due to combined paracrine and physical contact-mediated signals. Conclusions: We conclude that TGF-β is only one of the players that mediates the communication between PDAC cells and fibroblasts and controls the acquisition of aggressive phenotypes. Hence, these advanced in vitro models may be exploited to further investigate these events and to design innovative anti-PDAC therapies.
背景：癌细胞与癌相关成纤维细胞（CAFs）之间的相互作用是决定侵袭性促结缔组织增生型癌症（如胰腺导管腺癌，PDAC）快速进展、高侵袭性和化疗耐药性的关键因素。已知肿瘤细胞通过分泌转化生长因子β（TGF-β）等细胞因子将成纤维细胞重编程为CAFs。反过来，CAFs产生可溶性因子（包括在肌成纤维细胞型CAFs中起主要作用的TGF-β）促进肿瘤细胞的侵袭性和化疗耐药性。这种高度复杂性阻碍了人们对基质成纤维细胞与PDAC细胞之间TGFβ信号传导回路的清晰认识。方法：本研究通过使用仅允许旁分泌信号传导（transwell系统）或同时允许旁分泌及接触介导信号传导（3D球体）的共培养体系来解决这一问题。结果：我们发现TGF-β在正常人成纤维细胞活化为α-平滑肌肌动蛋白（α-SMA）阳性CAFs过程中起关键作用。CAFs释放的TGF-β可促进PDAC细胞增殖并增强其对吉西他滨的耐药性，同时伴随PDAC细胞发生部分上皮-间质转化，但其迁移能力并未增强。然而，由PDAC细胞与成纤维细胞构成的3D异质球体模型能够监测CAFs对癌细胞的促侵袭效应，这可能是旁分泌信号与物理接触介导信号共同作用的结果。结论：我们认为TGF-β仅是介导PDAC细胞与成纤维细胞间通讯并调控侵袭性表型获得的因素之一。因此，这些先进的体外模型可用于进一步研究这些生物学事件，并为设计创新的抗PDAC疗法提供平台。
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