Intratumoral Hepatic Stellate Cells as a Poor Prognostic Marker and a New Treatment Target for Hepatocellular CarcinomaReportar como inadecuado

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Hepatic stellate cells HSCs, a specialized stromal cytotype in the liver, have been demonstrated to actively contribute to hepatocellular carcinoma HCC development. However, the previous studies were performed using HSC cell lines, and the prognostic value of intratumoral HSCs tHSCs was unclear. Here we isolated tHSCs from fresh human HCC tissues, and analyzed the abilities of tHSCs to promote HCC progression by using in vitro assays for cell viability, migration and invasion as well as epithelial-mesenchymal transition EMT phenotype. 252 HCC patients who underwent hepatectomy were enrolled for analysis of tHSCs and E-cadherin expression in tumor tissues, and 55 HCC patients for analysis of tHSCs in tumor tissues and circulating tumor cells CTCs in blood. Prognostic factors were then identified. The results showed that coculture of tHSCs with HCC cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition EMT phenotype. In vivo cotransplantation of HCC cells with tHSCs into nude mice more efficiently promoted tumor formation and growth. Icaritin, a known apoptosis inducer of HSCs, was demonstrated to effectively inhibit tHSC proliferation in vitro and tHSC-induced HCC-promoting effects in vivo. Clinical evidence indicated that tHSCs were rich in 45% of the HCC specimens, tHSC-rich subtypes were negatively correlated either with E-cadherin expression in tumor tissues r = -0.256, p < 0.001 or with preoperative CTCs in blood r = -0.287, p = 0.033, and were significantly correlated with tumor size p = 0.027, TNM staging p = 0.018, and vascular invasion p = 0.008. Overall and recurrence-free survival rates of tHSC-rich patients were significantly worse than those for tHSC-poor patients. Multivariate analysis revealed tHSC-rich as an independent factor for overall and recurrence-free survival. In conclusion, tHSCs provide a promising prognostic biomarker and a new treatment target for HCC.

Autor: Bin Sun , Xiaofeng Zhang , Xianshuo Cheng, Yu Zhang, Lei Chen, Lehua Shi, Zhenyu Liu, Haihua Qian, Mengchao Wu, Zhengfeng Yin



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