Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Sarah P. Thayer (), Marina Pasca di Magliano, Patrick W. Heiser, Corinne M. Nielsen, Drucilla J. Roberts, Gregory Y. Lauwers, Yan Ping Qi, Stephan Gysin, Carlos Fernández-del Castillo, Vijay Yajnik, Bozena Antoniu, Martin McMahon, Andrew L. Warshaw and Matthias Hebrok ()
Additional contact information
Sarah P. Thayer: Massachusetts General Hospital and Harvard Medical School
Marina Pasca di Magliano: University of California
Patrick W. Heiser: University of California
Corinne M. Nielsen: Massachusetts General Hospital and Harvard Medical School
Drucilla J. Roberts: Massachusetts General Hospital and Harvard Medical School
Gregory Y. Lauwers: Massachusetts General Hospital and Harvard Medical School
Yan Ping Qi: University of California
Stephan Gysin: University of California
Carlos Fernández-del Castillo: Massachusetts General Hospital and Harvard Medical School
Vijay Yajnik: Massachusetts General Hospital and Harvard Medical School
Bozena Antoniu: Massachusetts General Hospital and Harvard Medical School
Martin McMahon: University of California
Andrew L. Warshaw: Massachusetts General Hospital and Harvard Medical School
Matthias Hebrok: University of California

Nature, 2003, vol. 425, issue 6960, 851-856

Abstract: Abstract Hedgehog signalling—an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer—may also be an important mediator in human pancreatic carcinoma1,2,3,4,5,6,7,8. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx–Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.

Date: 2003
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DOI: 10.1038/nature02009

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