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Cancer Res:TGF-β抑制胰腺癌发展

来源:生物谷 2012-07-28 20:26

早期研究显示由于TGF-β能促进癌细胞侵袭,建立一个促肿瘤发展的微环境。TGF-β途径是潜在的作为抗癌药物的靶点之一, 然而,TGF-β抑制剂的临床应用仍然不明朗,因为遗传研究表明胰腺癌和其他上皮型恶性肿瘤中TGF-β具有肿瘤抑制功能。

在一项新研究中,研究人员用遗传工程小鼠模型探讨TGF-β抑制剂对胰腺癌肿瘤各分期、基因序列和同步化疗治疗的影响。结果发现在胰脏癌中,整合素αvβ6是TGF-β的一个关键上游激活因子。此外,抑制TGF-β或αvβ6结果反而促进了肿瘤细胞的增殖。

这些影响依赖于Smad4的存在,是TGF-β信号的最关键调控因子。因此,研究结果表明,αvβ6和TGFβ以一个共同的方式抑制肿瘤,而这两个蛋白一旦受到抑制后会加速胰腺癌的发展。(生物谷:Bioon.com)

TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression

Aram F. Hezel1,*, Vikram Deshpande2, Stephanie M. Zimmerman3, et al.

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 advanced 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.

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