TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression

Cancer Res. 2012 Sep 15;72(18):4840-5. doi: 10.1158/0008-5472.CAN-12-0634. Epub 2012 Jul 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Immunohistochemistry
  • Integrins / metabolism*
  • Mice
  • Pancreatic Neoplasms / metabolism*
  • Signal Transduction / physiology*
  • Transforming Growth Factor beta / metabolism*


  • Antigens, Neoplasm
  • Integrins
  • Transforming Growth Factor beta
  • integrin alphavbeta6