Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin
Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin
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酸性肿瘤微环境激活肝星状细胞通过骨桥蛋白促进肝细胞癌转移
DOI：
10.1016/j.canlet.2014.10.021
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Qin, Wenxin
中科院分区：
文献类型：
--
作者：
Song, Jin;Ge, Zhouhong;Qin, Wenxin
由于糖酵解过度和灌注不良，实体瘤的细胞外pH通常呈酸性。但酸性肿瘤微环境是否影响基质细胞在肿瘤中的浸润尚不清楚。肝星状细胞（hepatic stellate cells，HSC）是肝脏基质细胞的主要祖细胞，其活化数量与肝癌患者肿瘤组织中的酸化水平呈正相关。而采用体外酸性培养条件和体内异种共移植模型研究HSC的反应及其对HCC进展的影响。在酸性培养条件下，HSC的活化依赖于细胞信号调节激酶（ERK）的磷酸化。酸活化的HSC在体内外均能促进肝癌转移。在酸性条件下，HSC分泌的骨桥蛋白（OPN）增加，并被证明促进HCC细胞的迁移。此外，OPN的表达水平与肌成纤维细胞显著相关，α-SMA与OPN的联合是HCC患者预后不良的有力预测因素。在酸性肿瘤微环境中激活HSC代表了HCC转移的新机制，并为HCC提供了潜在的治疗策略。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Extracellular pH of solid tumor is generally acidic due to excessive glycolysis and poor perfusion. But whether acidic tumor microenvironment influenced the stromal cells infiltrating in tumor remains unknown. As the predominant progenitor of stromal cells in liver, the number of activated hepatic stellate cells (HSCs) was found positively correlated to the acidification level in the tumor tissues of HCC patients in our study. Whereas, in vitro acidic culture condition and in vivo co-implanting xenograft model were adopted to study the response of HSCs and its influence on HCC progression. HSCs were activated under acidic culture condition depending on the phosphorylation of cellular signal-regulated kinase (ERK). Acidity-activated HSCs promoted HCC metastasis in vitro and in vivo. Osteopontin (OPN) excretion from HSCs was increased under acidic condition and proved to promote the migration of HCC cells. Furthermore, the expression level of OPN was significantly associated with myofibroblasts and the combination of alpha-SMA with OPN was a powerful predictor for poor prognosis of HCC patients. Activation of HSCs in acidic tumor microenvironment represents a novel mechanism for HCC metastasis and provides a potential therapeutic strategy for HCC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.