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 [1][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.Sonic hedgehog (SHH) is misexpressed in human adenocarcinoma and its precursor lesions. SHH expression was determined using in situ hybridization to detect SHH messenger RNA and immunohistochemistry (IHC) to detect the protein with an antibody directed against Competing interests statementThe authors declare that they have no competing financial interests. . Pancreatic tissues were obtained from 20 specimens resected for pancreatic cancer. Control pancreatic tissues with no evidence of abnormality or autolysis upon histological evaluation were obtained from autopsy specimens or from pancreatic resections for trauma. In normal adult human pancreata, no SHH was detected in the islets, acini or ductal epithelium (Fig. 1a). However, evaluation of pancreata from patients with adenocarcinoma reveals that SHH is aberrantly expressed in 70% of specimens. Normal ductal epithelium does not express detectable levels of SHH (Fig. 1b); however, as the ductal epithelium shows increasing degrees of atypia, PanIN-1 to -3 ( Fig. 1c-e), a higher expression of SHH is observed. SHH expression is also detected in the malignant epithelium of adenocarcinoma samples (Fig. 1f). This expression pattern was also confirmed by our in situ hybridization for SHH mRNA ( Supplementary Fig. 1). NIH Public AccessLoss of regulation in this pathway has been implicated in several human cancers 10,11 . Thus in order to determine the potential role of SHH misexpression in the adult human pancreas, pancreata from transgenic mice (gift of H. Edlund) in which Shh misexpression was driven by the pancreatic-specific Pdx-1 promoter were histologically and immunohistochemically analysed.A total of four pancreata from three-week-old Pdx-Shh mice were histologically evaluated by a gastro...

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