Innovation of cancer treatment based on the refractory mechanism

肝细胞癌（Hepatocellular carcinoma，HCC）是一种侵袭性恶性肿瘤，其主要原因是术后复发和/或转移，有证据表明肿瘤的转移和复发可能是由一小部分干细胞（cancer stem cells，CSCs）驱动的。先前的研究显示胶质瘤和乳腺CSC的蛋白酶体活性本来就很低。据报道，乳腺癌干细胞含有较低水平的活性氧（ROS）比相应的非致瘤细胞。我们观察到两个干细胞特征，低蛋白酶体活性和低细胞内ROSinHCC细胞。我们用双色流式细胞仪分选出具有这些干细胞特征的细胞，观察到一小部分HCC细胞呈现不对称分裂，它们在NOD/SCID小鼠体内的致瘤性表明HCC CSC具有致癌潜力，综合基因表达分析显示，在CSC亚群中，趋化因子相关基因表达上调。我们鉴定的HCC CSC在体外促进了巨噬细胞的迁移，并在体内证明了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CSC特异性基因签名与复发具有显著相关性。干细胞特征的监测系统是一个有前途的工具，以分析在人类肝癌中的CSC微环境的体内意义。

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.