Role of desmoplasia in cholangiocarcinoma and hepatocellular carcinoma
Role of desmoplasia in cholangiocarcinoma and hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2014.04.014
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发表时间：
2014-08-01
影响因子：
25.7
通讯作者：
Campbel, Jean S.
中科院分区：
文献类型：
--
作者：
Lee, Jung Il;Campbel, Jean S.
肝内胆管癌（CCA）的特点是丰富的促纤维增生环境。 CCA 的不良预后与基质中存在 α-平滑肌肌动蛋白 (α-SMA) 阳性肌成纤维细胞 (MF) 以及肿瘤细胞中表皮生长因子受体 (EGFR) 的持续激活有关。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，有助于多种癌症中 MF 和肿瘤细胞之间的细胞间通讯。本研究旨在测试肝脏 MF 是否通过 EGFR 信号传导促进 CCA 进展。首先使用免疫功能低下小鼠的皮下异种移植物在体内检查 CCA 细胞和肝脏 MF 之间的相互作用。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、大小和转移扩散。这些效应被 EGFR 酪氨酸激酶抑制剂吉非替尼消除。对人类 CCA 组织的免疫组织化学分析表明，基质 MF 表达 HB-EGF，而在癌细胞中检测到 EGFR。在体外，HLMF 产生 HB-EGF，其条件培养基诱导 EGFR 激活，促进 CCA 细胞中粘附连接的破坏、迁移和侵袭特性。当吉非替尼或 HB-EGF 中和抗体存在时，这些作用被消除。我们还表明，CCA 细胞产生转化生长因子 β 1，进而诱导 HLMF 中的 HB-EGF 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 进展。(C) 2014 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
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 (alpha-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 metastatic 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.( C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.