Department of Medicine, UC San Diego, La Jolla, CA 92093, USA.
Department of Surgery, UC San Diego, La Jolla, CA 92093, USA.
Int J Mol Sci. 2019 Apr 7;20(7):1723. doi: 10.3390/ijms20071723.
Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in liver fibrogenesis and hepatocarcinogenesis, respectively. CAFs, which probably derive from HSCs, activate into extracellular matrix (ECM)-producing myofibroblasts and crosstalk with cancer cells to affect tumor growth and invasion. In this review, we describe the different components which form the HCC premalignant microenvironment (PME) and the tumor microenvironment (TME), focusing on the liver fibrosis process and the biology of CAFs. We will describe the CAF-dependent mechanisms which have been suggested to promote hepatocarcinogenesis, such as the alteration of ECM, CAF-dependent production of cytokines and angiogenic factors, CAF-dependent reduction of immuno-surveillance, and CAF-dependent promotion of epithelial-mesenchymal transition (EMT). New knowledge of the fibrosis process and the role of CAFs in HCC may pave the way for new therapeutic strategies for liver cancer.
肝细胞癌（HCC）是最具侵袭性的癌症之一，缺乏有效的治疗方法。大多数 HCC 发生在慢性肝损伤、肝炎症和纤维化的背景下。肝星状细胞（HSCs）和癌相关成纤维细胞（CAFs）分别是肝纤维化和肝癌发生的关键参与者。CAFs 可能来源于 HSCs，激活为产生细胞外基质（ECM）的肌成纤维细胞，并与癌细胞相互作用，影响肿瘤的生长和侵袭。在这篇综述中，我们描述了形成 HCC 癌前微环境（PME）和肿瘤微环境（TME）的不同成分，重点介绍了肝纤维化过程和 CAFs 的生物学特性。我们将描述已被提出的促进肝癌发生的 CAF 依赖性机制，例如 ECM 的改变、CAF 依赖性细胞因子和血管生成因子的产生、CAF 依赖性免疫监视的减少以及 CAF 依赖性上皮间质转化（EMT）的促进。对纤维化过程和 CAFs 在 HCC 中的作用的新认识可能为肝癌的新治疗策略铺平道路。
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