Biology, Epidemiology, Clinical Aspects of Hepatocellular Carcinoma and the Role of Sorafenib
Biology, Epidemiology, Clinical Aspects of Hepatocellular Carcinoma and the Role of Sorafenib
复制标题
DOI：
10.2174/1389450117666151209120831
复制
发表时间：
2016-01-01
影响因子：
3.2
通讯作者：
Vinciguerra, Manlio
中科院分区：
文献类型：
--
作者：
Mazzoccoli, Gianluigi;Miele, Luca;Vinciguerra, Manlio
索拉非尼是细胞内酪氨酸和丝氨酸/苏氨酸蛋白激酶（VEGFR、PDGFR、CRAF和BRAF）的小分子抑制剂，也被认为可以诱导自噬，这是影响肿瘤生长的主要机制。索拉非尼在其他化疗药物难治性的不可切除肝细胞癌（HCC）的治疗中显示出疗效。HCC是慢性肝病的主要终点，也是癌症相关死亡的第三大原因。与安慰剂相比，索拉非尼可提高HCC患者的总生存率。在西方国家，影响多达30%人口的最常见慢性肝病是非酒精性脂肪性肝病（NAFLD），这是一种肝内甘油三酯积聚，被认为是胰岛素抵抗和肥胖的肝脏表现。NAFLD包括一系列肝脏损害等级的疾病，从脂肪变性到非酒精性脂肪性肝炎（NASH），以肝细胞损伤/炎症存在或不存在纤维化为特征。10%的NAFLD患者发展为NASH，并可能发展为肝硬化和HCC。最近令人兴奋的研究揭示了索拉非尼的潜在治疗作用，不仅限于HCC，还扩展到肝硬化期间的肝硬化门脉高压综合征，以及通过直接抑制活化的肝星状细胞（HSC）介导的选择性抗纤维化作用，HSC是肝内基质沉积的细胞介质。这篇综述的目的是简要总结我们目前对HCC的生物学、流行病学和临床方面的知识，以及之前被低估的索拉非尼治疗HCC的疗效。因此，该综述利用了肝脏疾病范围内的数据，包括从实验到临床前再到临床。
Sorafenib is a small molecular inhibitor of intracellular tyrosine and serine/threonine protein kinases (VEGFR, PDGFR, CRAF and BRAF), and is thought also to induce autophagy, a chief mechanism influencing tumor growth. Sorafenib shows efficacy in the management of non-resectable hepatocellular carcinoma (HCC), which is refractory to other chemotherapeutic drugs. HCC represents a major end point of chronic liver diseases and the third leading cause of cancer-related death. In HCC patients Sorafenib increases overall survival compared to placebo. The most common chronic liver disease affecting up to 30% of the population in Western countries is non-alcoholic fatty liver disease (NAFLD), an intra-hepatic amassing of triglycerides deemed as the hepatic manifestation of insulin resistance and obesity. NAFLD encompasses a range of disorders with grades of liver damage varying from steatosis to non-alcoholic steatohepatitis (NASH), hallmarked by hepatocellular injury/inflammation in the presence or not of fibrosis. NAFLD patients progress to NASH in 10% of cases, which may progress to cirrhosis and HCC. Recent exciting studies uncovered a potential therapeutic role for Sorafenib that goes beyond HCC, and extends to cirrhotic portal hypertensive syndrome during cirrhosis, and to selective anti-fibrotic effects mediated through direct inhibition of activated hepatic stellate cells (HSC), the cellular mediators of intra-hepatic matrix deposition. The aim of this review is to concisely summarize our current knowledge of the biology, epidemiology and clinical aspects of HCC, as well as the previously under-appreciated therapeutic efficacy of Sorafenib beyond HCC. The review therefore utilizes data along the spectrum of liver diseases, including from experimental via pre-clinical to clinical.