Innovation of cancer treatment based on the refractory mechanism

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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.