Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Sarah P. Thayer, Marina Pasea Di Magliano, Patrick W. Heiser, Corinne M. Nielsen, Drucilia J. Roberts, Gregory Y. Lauwers, Yan Ping Qi, Stephan Gysin, Carlos Fernández-del Castillo, Vijay Yajnik, Bozena Antoniu, Martin McMahon, Andrew L. Warshaw, Matthias Hebrok

Research output: Contribution to journalArticle

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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 carcinoma. 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.

Original languageEnglish (US)
Pages (from-to)851-856
Number of pages6
JournalNature
Volume425
Issue number6960
DOIs
StatePublished - Oct 23 2003

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Hedgehogs
Pancreatic Neoplasms
Carcinogenesis
Neoplasms
Adenocarcinoma
Cell Line
Endoderm
Mutation
Embryonic Development
Pancreas
Maintenance
Apoptosis
Ligands

ASJC Scopus subject areas

  • General

Cite this

Thayer, S. P., Di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts, D. J., Lauwers, G. Y., ... Hebrok, M. (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425(6960), 851-856. https://doi.org/10.1038/nature02009

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. / Thayer, Sarah P.; Di Magliano, Marina Pasea; Heiser, Patrick W.; Nielsen, Corinne M.; Roberts, Drucilia J.; Lauwers, Gregory Y.; Qi, Yan Ping; Gysin, Stephan; Fernández-del Castillo, Carlos; Yajnik, Vijay; Antoniu, Bozena; McMahon, Martin; Warshaw, Andrew L.; Hebrok, Matthias.

In: Nature, Vol. 425, No. 6960, 23.10.2003, p. 851-856.

Research output: Contribution to journalArticle

Thayer, SP, Di Magliano, MP, Heiser, PW, Nielsen, CM, Roberts, DJ, Lauwers, GY, Qi, YP, Gysin, S, Fernández-del Castillo, C, Yajnik, V, Antoniu, B, McMahon, M, Warshaw, AL & Hebrok, M 2003, 'Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis', Nature, vol. 425, no. 6960, pp. 851-856. https://doi.org/10.1038/nature02009
Thayer SP, Di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003 Oct 23;425(6960):851-856. https://doi.org/10.1038/nature02009
Thayer, Sarah P. ; Di Magliano, Marina Pasea ; Heiser, Patrick W. ; Nielsen, Corinne M. ; Roberts, Drucilia J. ; Lauwers, Gregory Y. ; Qi, Yan Ping ; Gysin, Stephan ; Fernández-del Castillo, Carlos ; Yajnik, Vijay ; Antoniu, Bozena ; McMahon, Martin ; Warshaw, Andrew L. ; Hebrok, Matthias. / Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. In: Nature. 2003 ; Vol. 425, No. 6960. pp. 851-856.
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