Hepatic Myofibroblasts Promote the Progression of Human Cholangiocarcinoma Through Activation of Epidermal Growth Factor Receptor
Hepatic Myofibroblasts Promote the Progression of Human Cholangiocarcinoma Through Activation of Epidermal Growth Factor Receptor
复制标题
DOI：
10.1002/hep.26585
复制
发表时间：
2013-12-01
期刊：
影响因子：
13.5
通讯作者：
Fouassier, Laura
中科院分区：
文献类型：
--
作者：
Claperon, Audrey;Mergey, Martine;Fouassier, Laura
肝内胆管细胞癌（CCA）的特点是有丰富的促纤维增生的环境。CCA的不良预后与间质中α-平滑肌肌动蛋白（-SMA）阳性肌成纤维细胞（MF）的存在以及肿瘤细胞中表皮生长因子受体（EGFR）的持续活化相关。在EGFR配体中，肝素结合表皮生长因子（HB-EGF）已成为一种旁分泌因子，在几种癌症中促进MF和肿瘤细胞之间的细胞间通讯。本研究旨在检测肝脏MF是否通过EGFR信号传导促进CCA进展。CCA细胞和肝MF之间的相互作用首先在体内进行了检查，使用皮下异种移植到免疫功能低下的小鼠。在这些实验中，CCA细胞与人肝肌成纤维细胞（HLMF）的共移植增加了肿瘤的发生率、大小和肿瘤的侵袭性扩散。这些作用被EGFR酪氨酸激酶抑制剂吉非替尼消除。人CCA组织的免疫组化分析显示，间质MFs表达HB-EGF，而EGFR在癌细胞中检测到。在体外，HLMF产生HB-EGF，其条件培养基诱导EGFR活化，促进CCA细胞粘附连接、迁移和侵袭特性的破坏。这些作用在吉非替尼或HB-EGF中和抗体的存在下被消除。我们还发现，CCA细胞产生转化生长因子β 1，这反过来又诱导HB-EGF在HLMF中的表达。结论：CCA细胞和肌成纤维细胞之间通过HB-EGF/EGFR轴的相互串扰有助于CCA的进展。（肝病学2013; 58：2001-2011）
Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant desmoplastic environment. Poor prognosis of CCA has been associated with the presence of alpha-smooth muscle actin (-SMA)-positive myofibroblasts (MFs) in the stroma and with the sustained activation of the epidermal growth factor receptor (EGFR) in tumor cells. Among EGFR ligands, heparin-binding epidermal growth factor (HB-EGF) has emerged as a paracrine factor that contributes to intercellular communications between MFs and tumor cells in several cancers. This study was designed to test whether hepatic MFs contributed to CCA progression through EGFR signaling. The interplay between CCA cells and hepatic MFs was examined first in vivo, using subcutaneous xenografts into immunocompromised mice. In these experiments, cotransplantation of CCA cells with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and metastastic dissemination of tumors. These effects were abolished by gefitinib, an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA tissues showed that stromal MFs expressed HB-EGF, whereas EGFR was detected in cancer cells. In vitro, HLMFs produced HB-EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions, migratory and invasive properties in CCA cells. These effects were abolished in the presence of gefitinib or HB-EGF-neutralizing antibody. We also showed that CCA cells produced transforming growth factor beta 1, which, in turn, induced HB-EGF expression in HLMFs. Conclusion: A reciprocal cross-talk between CCA cells and myofibroblasts through the HB-EGF/EGFR axis contributes to CCA progression. (Hepatology 2013; 58:2001-2011)