TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.
TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.
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DOI：
10.1158/0008-5472.can-12-0634
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发表时间：
2012-09-15
期刊：
影响因子：
11.2
通讯作者：
Bardeesy N
中科院分区：
文献类型：
--
作者：
Hezel AF;Deshpande V;Zimmerman SM;Contino G;Alagesan B;O'Dell MR;Rivera LB;Harper J;Lonning S;Brekken RA;Bardeesy N
tgf - β通路由于其促进癌细胞侵袭和创造促肿瘤微环境的能力而被积极考虑作为癌症药物靶点。然而，TGFβ抑制剂的临床应用仍然不确定，因为遗传学研究表明TGFβ在胰腺癌和其他上皮恶性肿瘤中具有肿瘤抑制功能。在这里，我们使用基因工程小鼠模型来研究tgf - β抑制在胰腺癌中的治疗作用与肿瘤分期、遗传谱和同期化疗的关系。我们发现αvβ6整合素在进化的胰腺癌中发挥了TGFβ上游激活因子的作用。此外，TGFβ或αvβ6阻断可增加肿瘤细胞增殖，加速疾病的早期和晚期阶段。这些作用依赖于Smad4的存在，Smad4是tgf - β信号传导的中心介质。因此，我们的研究结果表明αvβ6和TGFβ在一个共同的肿瘤抑制通路中起作用，其药物失活促进胰腺癌的进展。
The TGFβ pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a pro-tumorigenic microenvironment. However, the clinical application of TGFβ inhibitors remains uncertain as genetic studies demonstrate a tumor suppressor function of TGFβ in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGFβ inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that αvβ6 integrin acted as a key upstream activator of TGFβ in evolving pancreatic cancers. In addition, TGFβ or αvβ6 blockade increased tumor cell proliferation and accelerated both early and later disease stages. These effects were dependent on the presence of Smad4, a central mediator of TGFβ signaling. Therefore, our findings indicate that αvβ6 and TGFβ act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.