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Hedgehog/Ras interactions regulate early stages of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) constitutes a lethal disease that affects >30,000 people annually in the United States. Deregulation of Hedgehog signaling has been implicated in the pathogenesis of PDA. To gain insights into the role of the pathway during the distinct stages of pancreatic carcinogenesis, we established a mouse model in which Hedgehog signaling is activated specifically in the pancreatic epithelium. Transgenic mice survived to adulthood and developed undifferentiated carcinoma, indicating that epithelium-specific Hedgehog signaling is sufficient to drive pancreatic neoplasia but does not recapitulate human pancreatic carcinogenesis. In contrast, simultaneous activation of Ras and Hedgehog signaling caused extensive formation of pancreatic intraepithelial neoplasias, the earliest stages of human PDA tumorigenesis, and accelerated lethality. These results indicate the cooperation of Hedgehog and Ras signaling during the earliest stages of PDA formation. They also mark Hedgehog pathway components as relevant therapeutic targets for both early and advanced stages of pancreatic ductal neoplasia.

Pubmed ID: 17114586

Authors

  • Pasca di Magliano M
  • Sekine S
  • Ermilov A
  • Ferris J
  • Dlugosz AA
  • Hebrok M

Journal

Genes & development

Publication Data

November 15, 2006

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR45973
  • Agency: NCI NIH HHS, Id: CA112537-01
  • Agency: NCI NIH HHS, Id: CA87837
  • Agency: NIDDK NIH HHS, Id: DK60533-01A1
  • Agency: NCI NIH HHS, Id: P30 CA82103
  • Agency: NIDDK NIH HHS, Id: P30 DK63720
  • Agency: NCI NIH HHS, Id: R01 CA087837
  • Agency: NCI NIH HHS, Id: R01 CA087837-02S1
  • Agency: NCI NIH HHS, Id: R01 CA087837-07
  • Agency: NCI NIH HHS, Id: R01 CA112537
  • Agency: NIDDK NIH HHS, Id: R01 DK060533

Mesh Terms

  • Animals
  • Epithelial Cells
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins
  • Humans
  • Mice
  • Mortality
  • Mutation
  • Neoplasm Staging
  • Pancreas
  • Pancreatic Neoplasms
  • Protein Binding
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction
  • Stromal Cells
  • Transgenes
  • Tumor Markers, Biological