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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-09, Vol.72 (18), p.4840-4845
• Main Authors: HEZEL, Aram F, DESHPANDE, Vikram, BARDEESY, Nabeel, ZIMMERMAN, Stephanie M, CONTINO, Gianmarco, ALAGESAN, Brinda, O'DELL, Michael R, RIVERA, Lee B, HARPER, Jay, LONNING, Scott, BREKKEN, Rolf A
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - metabolism; Antineoplastic agents; Biological and medical sciences; Disease Models, Animal; Disease Progression; Gastroenterology. Liver. Pancreas. Abdomen; Immunohistochemistry; Integrins - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Pancreatic Neoplasms - metabolism; Pharmacology. Drug treatments; Signal Transduction - physiology; Transforming Growth Factor beta - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-0634

The TGF-β 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-β inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-β in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-β 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 TGF-β in evolving pancreatic cancers. In addition, TGF-β 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 TGF-β signaling. Therefore, our findings indicate that αvβ6 and TGF-β act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.