TGF- and v 6 Integrin Act in a Common Pathway to Suppress Pancreatic Cancer Progression

and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Cancer Research (Impact Factor: 9.33). 07/2012; 72(18):4840-5. DOI: 10.1158/0008-5472.CAN-12-0634
Source: PubMed


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. Cancer Res; 72(18); 4840-5. ©2012 AACR.

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    • "The role of αvβ6-dependent TGFβ activation in cancer has been investigated in a number of studies [31], [32], [33], [34], [35], that illustrate both the potential and complexity associated with this target. For example, when αvβ6 was blocked with antibodies in the early stages of disease in a transgenic pancreatic cancer mouse model, this accelerated cancer progression when SMAD4 was functional, but not in SMAD4-null animals [34]. "
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