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

Aram F. Hezel, Vikram Deshpande, Stephanie M. Zimmerman, Gianmarco Contino, Brinda Alagesan, Michael R. O'Dell, Lee B. Rivera, Jay Harper, Scott Lonning, Rolf A. Brekken, Nabeel Bardeesy

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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 avb6 and TGF-β act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.

Original languageEnglish (US)
Pages (from-to)4840-4845
Number of pages6
JournalCancer research
Volume72
Issue number18
DOIs
StatePublished - Sep 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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