Authors' Affiliations: Department of Biomedical Science and Human Oncology, University of Bari Medical School, Bari; Department of Internal Medicine, University of Modena and Reggio, Modena, Italy; and Early Phase Clinical Investigation, Eli Lilly and Company, Indianapolis, Indiana.
Cancer Res. 2014 Apr 1;74(7):1890-4. doi: 10.1158/0008-5472.CAN-14-0243. Epub 2014 Mar 17.
Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-β plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition (EMT). TGF-β signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-β signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-β signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGF-β signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-β inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT.
肝细胞癌是在长期存在的肝脏疾病患者中发生的，包括病毒性肝炎、酗酒或代谢疾病。在这些先前存在的肝脏疾病中，TGF-β 在为肿瘤细胞生长和促进上皮间质转化（EMT）创造有利的微环境方面发挥着重要作用。TGF-β 信号通过两种机制促进肝细胞癌的进展：首先，通过作为自分泌或旁分泌生长因子的内在活性，其次，通过诱导微环境变化，包括癌相关成纤维细胞、T 调节细胞和炎症介质，发挥外源性活性。尽管越来越了解 TGF-β 信号与肝细胞癌中的肿瘤进展相关，但尚不清楚 TGF-β 信号是否仅限于肝细胞癌的特定亚组患者，或者是否是肝细胞癌整个癌变过程中的关键驱动因素。在不同的实验模型中，TGF-β 信号抑制剂通过调节 EMT 已被证明可以阻止肝细胞癌的生长和进展，导致 TGF-β 抑制剂 LY2157299 一水合物在肝细胞癌中的临床研究。一项 II 期临床试验的初步结果显示，临床结果得到改善，并且与 EMT 减少一致的变化。
