Journal
CANCER RESEARCH
Volume 72, Issue 18, Pages 4840-4845Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-12-0634
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Funding
- Imclone Systems
- Genzyme
- Stromedix
- HHMI Early Career Award
- NCI [KO8 CA122835-03]
- NIH [NCI 2P01CA117969-06, NCI 1R01 CA133557-01, P50CA127003]
- Lynda Verville Cancer Research Foundation
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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.
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