Innovation of cancer treatment based on the refractory mechanism

肝细胞癌（HCC）是一种侵袭性恶性肿瘤，主要是由于治愈性切除后复发和/或转移所致。越来越多的证据表明，肿瘤转移和复发可能是由一小部分干细胞（即所谓的癌症干细胞（CSC））驱动的。先前的研究表明，神经胶质瘤和乳腺 CSC 表现出本质上较低的蛋白酶体活性。据报道，乳腺 CSC 的活性氧 (ROS) 水平低于相应的非致瘤细胞。我们观察了 HCC 细胞中的两个干细胞特征：低蛋白酶体活性和低细胞内 ROS。我们使用双色 FACS 分选来分离具有这些干细胞特征的细胞。可视化的 HCC 细胞小亚群显示出不对称分裂。它们在 NOD/SCID 小鼠中显着的致瘤性表明 HCCCSC 具有癌症起始潜力。综合基因表达分析表明，趋化因子相关基因在 CSC 亚群中上调。我们鉴定的 HCC CSC 促进了体外巨噬细胞的迁移，并证明了体内巨噬细胞募集的转移潜力。在 HCC 根治性手术后的患者中，肝脏微环境中的 CSC 特异性基因特征与复发具有显着相关性。干细胞特征的监测系统是分析人类肝癌中 CSC 微环境的体内重要性的有前途的工具。

Hepatocellular carcinoma (HCC) is one of the aggressive malignancies mainly due to the recurrence and/or metastasisevenaftercurativeresection.Thereis emergingevidencethattumormetastasisand recurrencemight be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). PreviousinvestigationsrevealedthatgliomaandbreastCSCswerefoundtoexhibitintrinsicallylowproteasomeactivity. It was reported that breast CSCs contained lower level of reactive oxygen species (ROS) than corresponding non-tumorigenic cells. We visualized two stem cell features, low proteasome activity and low intracellular ROSinHCCcells. We usedtwo-color FACSsortingtoisolatethecellswith these stemcellfeatures.Avisualized smallsubpopulationofHCCcellsdemonstratedasymmetricdivisions.TheirremarkabletumorigenicityinNOD/SCID micesuggestedthecancerinitiation potentialofthe HCCCSCs.Comprehensivegeneexpression analysisrevealedthat chemokine-related genes were upregulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro, and demonstrated the metastatic potentials with recruitment of macrophages in vivo. In the patients after curative operation for HCC, the CSC-specific gene signature in the liver microenvironments has a significant correlation to the recurrence. The monitoring system of the stem cell features is a promising tool to analyze the in vivo significance of CSCs microenvironments in human HCC.