TGF-β and αvβ6 Integrin Act in a Common Pathway to Suppress Pancreatic Cancer Progression

The TGF-beta pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-beta inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-beta in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-beta inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that alpha v beta 6 integrin acted as a key upstream activator of TGF-beta in evolving pancreatic cancers. In addition, TGF-beta or alpha v beta 6 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 TGF-beta signaling. Therefore, our findings indicate that alpha v beta 6 and TGF-beta act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression. Cancer Res; 72(18); 4840-5. (C)2012 AACR.