Chen Siqi, Du Yaqing, Guan Xin-Yuan, Yan Qian
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Oncol. 2023 Jul 27;13:1204513. doi: 10.3389/fonc.2023.1204513. eCollection 2023.
Hepatocellular carcinoma (HCC) is a heterogeneous and aggressive liver cancer that presents limited treatment options. Despite being the standard therapy for advanced HCC, sorafenib frequently encounters resistance, emphasizing the need to uncover the underlying mechanisms and develop effective treatments. This comprehensive review highlights the crucial interplay between the tumor microenvironment, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT) in the context of sorafenib resistance. The tumor microenvironment, encompassing hypoxia, immune cells, stromal cells, and exosomes, exerts a significant impact on HCC progression and therapy response. Hypoxic conditions and immune cell infiltration create an immunosuppressive milieu, shielding tumor cells from immune surveillance and hindering therapeutic efficacy. Additionally, the presence of CSCs emerges as a prominent contributor to sorafenib resistance, with CD133+ CSCs implicated in drug resistance and tumor initiation. Moreover, CSCs undergo EMT, a process intimately linked to tumor progression, CSC activation, and further promotion of sorafenib resistance, metastasis, and tumor-initiating capacity. Elucidating the correlation between the tumor microenvironment, CSCs, and sorafenib resistance holds paramount importance in the quest to develop reliable biomarkers capable of predicting therapeutic response. Novel therapeutic strategies must consider the influence of the tumor microenvironment and CSC activation to effectively overcome sorafenib resistance in HCC.
肝细胞癌（HCC）是一种异质性且侵袭性强的肝癌，治疗选择有限。尽管索拉非尼是晚期HCC的标准疗法，但它经常会出现耐药性，这凸显了揭示其潜在机制并开发有效治疗方法的必要性。这篇综述强调了在索拉非尼耐药背景下肿瘤微环境、癌症干细胞（CSCs）和上皮-间质转化（EMT）之间的关键相互作用。肿瘤微环境包括缺氧、免疫细胞、基质细胞和外泌体，对HCC的进展和治疗反应有重大影响。缺氧条件和免疫细胞浸润形成免疫抑制环境，保护肿瘤细胞免受免疫监视并阻碍治疗效果。此外，CSCs的存在是索拉非尼耐药的一个重要因素，CD133+ CSCs与耐药性和肿瘤起始有关。此外，CSCs会经历EMT，这一过程与肿瘤进展、CSC激活以及索拉非尼耐药性、转移和肿瘤起始能力的进一步增强密切相关。阐明肿瘤微环境、CSCs和索拉非尼耐药性之间的相关性对于开发能够预测治疗反应的可靠生物标志物至关重要。新的治疗策略必须考虑肿瘤微环境和CSC激活的影响，以有效克服HCC中的索拉非尼耐药性。
