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Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

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.

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Figure 1: Immunohistochemical identification of SHH.
Figure 2: Histological comparison of human PanINs and Pdx–Shh mouse pancreata.
Figure 3: Hedgehog signalling pathway.
Figure 4: Effects of cyclopamine treatment on pancreatic adenocarcinoma cells.
Figure 5: Cyclopamine treatment blocks tumour formation of human pancreatic adenocarcinoma cells after transplantation into nude mice.

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Acknowledgements

S.P.T. and co-workers are grateful to D. A. Melton and P. A. Donahoe for discussion and review of the manuscript; H. Edlund for supplying the construct and initial pancreatic tissue for the Pdx–Shh transgenic mouse; and C. Tabin for the Shh in situ probe. We also thank N. Frost for editorial assistance. This work was supported in part by a grant from the Lustgarten Foundation to S.P.T. M.H. and co-workers thank C. Basbaum, D. Hanahan, I. Herskowitz, T. Kornberg, M. Tempero and members of the Hebrok laboratory for discussions and comments on the manuscript. We thank L. Jaffee for provision of the Panc series of cells. We are grateful to L. Spector for editorial assistance. This work was supported by grants to M.H. from the Juvenile Diabetes Foundation and the National Institutes of Health.

Authors' contributions S.P.T. and M.H. are senior authors.

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Correspondence to Sarah P. Thayer or Matthias Hebrok.

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Thayer, S., di Magliano, M., Heiser, P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003). https://doi.org/10.1038/nature02009

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