早期研究顯示由于TGF-β能促進癌細胞侵襲，建立一個促腫瘤發(fā)展的微環(huán)境,。TGF-β途徑是潛在的作為抗癌藥物的靶點之一,， 然而，TGF-β抑制劑的臨床應用仍然不明朗,，因為遺傳研究表明胰腺癌和其他上皮型惡性腫瘤中TGF-β具有腫瘤抑制功能,。
在一項新研究中，研究人員用遺傳工程小鼠模型探討TGF-β抑制劑對胰腺癌腫瘤各分期,、基因序列和同步化療治療的影響,。結果發(fā)現在胰臟癌中，整合素αvβ6是TGF-β的一個關鍵上游激活因子,。此外,，抑制TGF-β或αvβ6結果反而促進了腫瘤細胞的增殖。
這些影響依賴于Smad4的存在,，是TGF-β信號的最關鍵調控因子,。因此，研究結果表明,，αvβ6和TGFβ以一個共同的方式抑制腫瘤,，而這兩個蛋白一旦受到抑制后會加速胰腺癌的發(fā)展。（生物谷：Bioon.com）
doi:10.1158/0008-5472.CAN-12-0634
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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.
