肝癌干细胞分子标志物和干性维持机制研究进展

Molecular markers and mechanisms for stemness maintenance of liver cancer stem cells: a review

摘要:

原发性肝癌是一种发生在肝脏的侵袭性肿瘤，具有极易发生转移和复发的特点。原发性肝癌主要包括肝细胞癌、肝内胆管癌、混合肝细胞胆管癌和纤维板层型肝细胞癌等。目前，手术切除、放射性和化学治疗仍是肝癌治疗的主要手段，但其特异性差、临床效果有限，肝癌患者5年总生存率仅为18%。肝癌干细胞是存在于肝癌组织中特定的细胞亚群，具有自我更新能力和强致瘤性，驱动肝癌起始、转移、耐药和复发。因此，肝癌干细胞分子标志物的鉴定及其干性维持机制的阐明，不仅能够揭示肝癌发病的分子机理，也为肝癌的分子分型、预后评估和靶向治疗奠定了理论基础。最新研究表明，5-氟尿嘧啶与CD13抑制剂联合使用，能够抑制CD13+肝癌干细胞的增殖，从而减少肿瘤体积。因此，肝癌干细胞是非常有前景的治疗靶标。文中将从分子标志物、干性维持机制及靶向治疗方面总结肝癌干细胞的最新进展。

Abstract:

Primary liver cancer (PLC) is an aggressive tumor and prone to metastasize and recur. According to pathological features, PLC are mainly categorized into hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, and fibrolamelic hepatocellular carcinoma, etc. At present, surgical resection, radiotherapy and chemotherapy are still the main treatments for PLC, but the specificities are poor and the clinical effects are limited with a 5-year overall survival rate of 18%. Liver cancer stem cells (LCSCs) are a specific cell subset existing in liver cancer tissues. They harbor the capabilities of self-renewal and strong tumorigenicity, driving tumor initiation, metastasis, drug resistance and recurrence of PLC. Therefore, the identification of molecular markers and the illustration of mechanisms for stemness maintenance of LCSCs can not only reveal the molecular mechanisms of PLC tumorigenesis, but also lay a theoretical foundation for the molecular classification, prognosis evaluation and targeted therapy of PLC. The latest research showed that the combination of 5-fluorouracil and CD13 inhibitors could inhibit the proliferation of CD13+ LCSCs, thereby reducing overall tumor burden. Taken together, LCSCs could be the promising therapeutic targets of PLC in the future. This review summarizes the latest progress in molecular markers, mechanisms for stemness maintenance and targeted therapies of LCSCs.