Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells.
Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells.
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DOI：
10.1002/hep.24588
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发表时间：
2011-12
期刊：
影响因子：
13.5
通讯作者：
Gores, Gregory J.
中科院分区：
文献类型：
--
作者：
Fingas, Christian D.;Bronk, Steven F.;Werneburg, Nathan W.;Mott, Justin L.;Guicciardi, Maria E.;Cazanave, Sophie C.;Mertens, Joachim C.;Sirica, Alphonse E.;Gores, Gregory J.
胆管癌（CCA）细胞矛盾地表达死亡配体TRAIL，因此，依赖于有效的生存信号来规避TRAIL细胞毒性。CCA也是具有富含肌成纤维细胞（MFB）的肿瘤微环境的高度促纤维增生性癌症。在此，我们研究了MFB衍生的CCA生存信号的作用。我们采用人KMCH-1、KMBC、HuCCT-1、TFK-1和Mz-ChA-1 CCA细胞以及人原代肝星状细胞和肌纤维母细胞LX-2细胞进行这些研究。使用同系大鼠原位CCA模型进行体内实验。CCA细胞与肌纤维母细胞性人原代HSC或LX-2细胞共培养显著降低了CCA细胞中TRAIL诱导的细胞凋亡，这种细胞保护作用可通过中和PDGF-BB抗血清消除。PDGF-BB的细胞保护作用依赖于Hedgehog（Hh）信号传导，因为它被smoothened（Hh信号传导的转导子）抑制剂环巴胺消除。PDGF-BB诱导PKA依赖性smoothened运输至质膜，导致GLI 2核转位和基于共有GLI报告基因的荧光素酶测定的激活。全基因组mRNA表达分析鉴定了67个靶基因，在CCA细胞中SHH和PDGF-BB以环巴胺依赖性方式共同上调（50个基因）或下调（17个基因）。最后，在啮齿动物CCA体内模型中，环巴胺给药增加CCA细胞的凋亡，导致肿瘤抑制。肌成纤维细胞来源的PDGF-BB通过Hh信号依赖性过程保护CCA细胞免受TRAIL细胞毒性。这些结果对人胆管癌的治疗具有治疗意义。
Cholangiocarcinoma (CCA) cells paradoxically express the death ligand TRAIL, and, therefore, are dependent upon potent survival signals to circumvent TRAIL cytotoxicity. CCAs are also highly desmoplastic cancers with a tumor microenvironment rich in myofibroblasts (MFBs). Herein, we examine a role for MFB-derived CCA survival signals. We employed human KMCH-1, KMBC, HuCCT-1, TFK-1, and Mz-ChA-1 CCA cells as well as human primary hepatic stellate and myofibroblastic LX-2 cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. Co-culturing CCA cells with myofibroblastic human primary HSCs or LX-2 cells significantly decreased TRAIL-induced apoptosis in CCA cells, a cytoprotective effect abrogated by neutralizing PDGF-BB-antiserum. Cytoprotection by PDGF-BB was dependent upon Hedgehog (Hh) signaling as it was abolished by the smoothened (the transducer of Hh signaling) inhibitor cyclopamine. PDGF-BB induced PKA-dependent trafficking of smoothened to the plasma membrane resulting in GLI2 nuclear translocation and activation of a consensus GLI reporter gene-based luciferase assay. A genome-wide mRNA expression analysis identified 67 target genes to be commonly up- (50 genes) or downregulated (17 genes) by both SHH and PDGF-BB in a cyclopamine-dependent manner in CCA cells. Finally, in a rodent CCA in vivo-model, cyclopamine administration increased apoptosis in CCA cells resulting in tumor suppression. Myofibroblast-derived PDGF-BB protects CCA cells from TRAIL cytotoxicity by a Hh signaling-dependent process. These results have therapeutical implications for the treatment of human cholangiocarcinoma.
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影响因子：
13.5
作者：
Dranoff, Jonathan A.;Wells, Rebecca G.
通讯作者：
Wells, Rebecca G.
DOI：
10.1073/pnas.0401064101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kuperwasser, C;Chavarria, T;Weinberg, RA
通讯作者：
Weinberg, RA
影响因子：
4.8
作者：
Deming, Paula B.;Campbell, Shirley L.;Howe, Alan K.
通讯作者：
Howe, Alan K.
胆管癌：发病机理，诊断和治疗的进展。
影响因子：
13.5
作者：
Blechacz, Boris;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
2.4
作者：
Fingas, Christian Dominik;Katsounas, Antonios;Canbay, Ali
通讯作者：
Canbay, Ali