Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer.
Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer.
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DOI：
10.18632/oncotarget.20822
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发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Apte MV
中科院分区：
文献类型：
--
作者：
Pothula SP;Xu Z;Goldstein D;Merrett N;Pirola RC;Wilson JS;Apte MV
胰腺癌（PC）中的基质-肿瘤相互作用对治疗结果的影响。胰腺星状细胞（PSC）产生PC的胶原基质，并与癌细胞相互作用以促进疾病进展。可能介导这种相互作用的候选生长因子途径是肝细胞生长因子（HGF）/c-MET途径。HGF由PSC产生，其受体c-MET在胰腺癌细胞上表达。我们研究了在存在和不存在代表性化疗剂吉西他滨的情况下抑制HGF/c-MET通路对PC进展的影响。使用PC的原位模型，我们已经表明，与单独或双重组合的每种治疗相比，“三联疗法”（HGF和c-MET两者的抑制与吉西他滨组合）导致肿瘤体积的最大减小。重要的是，在接受三联疗法的小鼠中几乎消除了转移。我们的体内研究结果得到了体外研究的支持，体外研究表明，三重方案显著抑制了PSC分泌物引起的癌细胞增殖和迁移的增加。我们的研究表明，通过化疗靶向肿瘤细胞，同时抑制介导基质-肿瘤相互作用的特定途径的联合方法可能代表了改善PC结局的新治疗策略。
Stromal-tumor interactions in pancreatic cancer (PC) impact on treatment outcomes. Pancreatic stellate cells (PSCs) produce the collagenous stroma of PC and interact with cancer cells to facilitate disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells. We studied the effects on PC progression of inhibiting the HGF/c-MET pathway in the presence and absence of a representative chemotherapeutic agent, gemcitabine. Using an orthotopic model of PC we have shown that “triple therapy” (inhibition of both HGF and c-MET combined with gemcitabine) resulted in the greatest reduction in tumor volume compared to each of the treatments alone or in dual combinations. Importantly, metastasis was virtually eliminated in mice receiving triple therapy. Our in vivo findings were supported by in vitro studies showing that the increase in cancer cell proliferation and migration in response to PSC secretions was significantly inhibited by the triple regimen. Our studies suggest that a combined approach, that targets tumor cells by chemotherapy while inhibiting specific pathways that mediate stromal-tumor interactions, may represent a novel therapeutic strategy to improve outcomes in PC.
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影响因子：
29.4
作者：
Apte MV;Wilson JS;Lugea A;Pandol SJ
通讯作者：
Pandol SJ
影响因子：
4.6
作者：
Byun JY;Youn YS;Lee YJ;Choi YH;Woo SY;Kang JL
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Kang JL
影响因子：
11.2
作者：
Matsushita, Arikira;Gotze, Tobias;Korc, Murray
通讯作者：
Korc, Murray
影响因子：
29.4
作者：
Li, Chenwei;Wu, Jing-Jiang;Simeone, Diane M.
通讯作者：
Simeone, Diane M.
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.