TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.
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.
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Aram F
AF
Hezel
Vikram
V
Deshpande
Stephanie M
SM
Zimmerman
Gianmarco
G
Contino
Brinda
B
Alagesan
Michael R
MR
O'Dell
Lee B
LB
Rivera
Jay
J
Harper
Scott
S
Lonning
Rolf A
RA
Brekken
Nabeel
N
Bardeesy
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6