肿瘤微环境介导肝细胞癌索拉非尼耐药的研究进展

Recent Progress on Sorafenib Resistance in Hepatocellular Carcinoma Mediated by Tumor Microenvironment

肝细胞癌(Hepatocellular carcinoma,HCC)是全球最常见的恶性肿瘤之一,约占原发性肝癌的90%,并且HCC的发病率仍在逐年增加。索拉非尼是一种多靶点酪氨酸激酶抑制剂,通过抑制肿瘤细胞增殖及肿瘤新生血管形成发挥抗HCC作用。因其可显著延长HCC患者的总生存期,索拉非尼已被批准作为晚期HCC患者的一线系统治疗药物。然而,仍有大量HCC患者对索拉非尼表现出原发及获得性耐药,导致这部分患者的预后更差。研究显示,HCC患者的肿瘤微环境与其对索拉非尼产生耐药密切相关,因此,亟需阐明肿瘤微环境介导HCC患者对索拉非尼产生耐药的机制并开发干预策略。肿瘤微环境由各种细胞及非细胞成分组成,如肿瘤相关巨噬细胞、肿瘤相关成纤维细胞、肿瘤相关中性粒细胞、细胞外基质、细胞因子和趋化因子。这些成分相互作用,并与肿瘤细胞形成一个相互作用的网络,调节HCC的生物学行为和对索拉非尼的反应。基于目前对肿瘤微环境介导肝细胞癌索拉非尼耐药的研究进展,文章综述了肿瘤微环境介导肝细胞癌索拉非尼耐药的机制,主要侧重于缺氧、肿瘤相关免疫抑制细胞、肿瘤相关成纤维细胞及克服索拉非尼耐药的潜在策略,如靶向肿瘤微环境中涉及的关键分子及通路,以及使用生物标志物来预测索拉非尼反应和选择最佳治疗方案,为未来临床治疗肝细胞癌患者提供新的思路,以期延长HCC患者的总生存期。

Hepatocellular carcinoma(HCC)was one of the most common malignant tumors in the world,accounting for about 90%of primary liver cancers,and the incidence of HCC were increasing year by year.Sorafenib,a multi-targeted tyrosine kinase inhibitor,had played an anti-HCC role by inhibiting tumor cell proliferation,tumor neovascularization,and tumor microenvironment remode-ling.Sorafenib had been approved as a first-line systematic therapy for advanced HCC patients,significantly prolonging the overall survival of some HCC patients.However,a large number of HCC patients still exhibited primary and acquired resistance to sorafenib,resulting in a worse prognosis for this patient population.Therefore,it was urgent to elucidate the mechanism of tumor microenviron-ment mediating the development of sorafenib resistance in HCC patients and develop intervention strategies.Studies have shown that the tumor microenvironment of HCC patients was closely related to the development of sorafenib resistance.The tumor microenviron-ment consisted of various cellular and non-cellular components,such as tumor-associated macrophages,cancer-associated fibroblasts,tumor-associated neutrophils,extracellular matrix,cytokines,and chemokines.These components interacted with each other and with tumor cells,forming a complex network that modulated the biological behavior and drug response of HCC.The mechanism of sorafenib resistance mediated by tumor microenvironment in hepatocellular carcinoma was reviewed in this article,mainly focusing on hypoxia,tumor-associated immune-suppressive cells and cancer-associated fibroblasts.Based on the current understanding of the mechanism of sorafenib resistance mediated by tumor microenvironment in hepatocellular carcinoma,this article also discussed the potential strate-gies to overcome sorafenib resistance,such as targeting the key molecules or pathways involved in the tumor microenvironment,and using biomarkers to predict the sorafenib response and select the optimal treatment regimen.This article aimed to provide new ideas for the clinical treatment of hepatocellular carcinoma patients in the future and in order to prolong the overall survival of HCC patients.