J Clin Invest. 2014 Jan;124(1):338-52. doi: 10.1172/JCI71526. Epub 2013 Dec 16.
Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-β. Given its tumor suppressor functions, it is unclear whether TGF-β is a valid therapeutic target for PDAC. Here, we found that proliferating pancreatic cancer cells (PCCs) from human PDAC patients and multiple murine models of PDAC (mPDAC) often exhibit abundant levels of phosphorylated retinoblastoma 1 (RB) and Smad2. TGF-β1 treatment enhanced proliferation of PCCs isolated from KrasG12D-driven mPDAC that lacked RB (KRC cells). This mitogenic effect was abrogated by pharmacological inhibition of type I TGF-β receptor kinase, combined inhibition of MEK/Src or MEK/PI3K, and restoration of RB expression. TGF-β1 promoted epithelial-to-mesenchymal transition (EMT), invasion, Smad2/3 phosphorylation, Src activation, Wnt reporter activity, and Smad-dependent upregulation of Wnt7b in KRC cells. Importantly, TGF-β1-induced mitogenesis was markedly attenuated by inhibition of Wnt secretion. In an in vivo syngeneic orthotopic model, inhibition of TGF-β signaling suppressed KRC cell proliferation, tumor growth, stroma formation, EMT, metastasis, ascites formation, and Wnt7b expression, and markedly prolonged survival. Together, these data indicate that RB dysfunction converts TGF-β to a mitogen that activates known oncogenic signaling pathways and upregulates Wnt7b, which synergize to promote PCC invasion, survival, and mitogenesis. Furthermore, this study suggests that concomitantly targeting TGF-β and Wnt7b signaling in PDAC may disrupt these aberrant pathways, which warrants further evaluation in preclinical models.
胰腺导管腺癌 (PDAC) 常伴有 TGF-β的过度表达。鉴于其肿瘤抑制功能,TGF-β 是否是 PDAC 的有效治疗靶点尚不清楚。在这里,我们发现来自人类 PDAC 患者和多种 PDAC 小鼠模型 (mPDAC) 的增殖性胰腺癌细胞 (PCC) 常表现出丰富水平的磷酸化视网膜母细胞瘤 1 (RB) 和 Smad2。TGF-β1 处理增强了缺乏 RB (KRC 细胞) 的 KrasG12D 驱动的 mPDAC 分离的 PCC 的增殖。这种促有丝分裂作用被 I 型 TGF-β 受体激酶的药理学抑制、MEK/Src 或 MEK/PI3K 的联合抑制以及 RB 表达的恢复所阻断。TGF-β1 促进了上皮-间充质转化 (EMT)、侵袭、Smad2/3 磷酸化、Src 激活、Wnt 报告基因活性以及 KRC 细胞中 Smad 依赖性 Wnt7b 的上调。重要的是,Wnt 分泌的抑制显著减弱了 TGF-β1 诱导的有丝分裂。在体内同源原位模型中,抑制 TGF-β 信号转导抑制了 KRC 细胞的增殖、肿瘤生长、基质形成、EMT、转移、腹水形成和 Wnt7b 的表达,并显著延长了生存期。总之,这些数据表明,RB 功能障碍将 TGF-β转化为一种有丝分裂原,激活已知的致癌信号通路并上调 Wnt7b,这协同促进 PCC 的侵袭、存活和有丝分裂。此外,这项研究表明,在 PDAC 中同时靶向 TGF-β和 Wnt7b 信号可能会破坏这些异常途径,这值得在临床前模型中进一步评估。