Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma.
Pasca di Magliano
Marina
M
Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California, United States of America.
Biankin
Andrew V
AV
Heiser
Patrick W
PW
Cano
David A
DA
Gutierrez
Pedro J A
PJ
Deramaudt
Therese
T
Segara
Davendra
D
Dawson
Amanda C
AC
Kench
James G
JG
Henshall
Susan M
SM
Sutherland
Robert L
RL
Dlugosz
Andrzej
A
Rustgi
Anil K
AK
Hebrok
Matthias
M
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
D053823:Hedgehog Proteins; D051153:Wnt Proteins