自分泌信号
癌症研究
生物
转化生长因子
肿瘤进展
间质细胞
转移
上皮-间质转换
CXCR4型
细胞因子
间充质干细胞
趋化因子
旁分泌信号
细胞迁移
转化生长因子β
趋化因子受体
趋化因子受体
细胞生物学
细胞
免疫学
癌症
受体
炎症
生物化学
遗传学
作者
Esther Bertrán,Eva Crosas‐Molist,Patricia Sancho,Laia Caja,Judit López‐Luque,Estanis Navarro,Gustavo Egea,Raquel Lastra,Teresa Serrano,Emilio Ramos,Isabel Fabregat
出处
期刊:Hepatology
[Wiley]
日期:2013-10-11
卷期号:58 (6): 2032-2044
被引量:116
摘要
Transforming growth factor-beta (TGF-β) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine by inducing other processes, such as the epithelial-mesenchymal transition (EMT), which contributes to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the center not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α) / chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF-β in human liver tumor cells correlates with a mesenchymal-like phenotype, resistance to TGF-β-induced suppressor effects, and high expression of CXCR4, which is required for TGF-β-induced cell migration. Silencing of the TGF-β receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mouse model of hepatocarcinogenesis (diethylnitrosamine-induced), tumors showed increased activation of the TGF-β pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma tumors, high levels of CXCR4 always correlated with activation of the TGF-β pathway, a less differentiated phenotype, and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination.A crosstalk exists among the TGF-β and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the protumorigenic effects of TGF-β and opens new perspectives for tumor therapy.
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