title: 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 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.
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. sthayer@partners.org
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Thayer
authors.forename: Marina Pasca
authors.initials: MP
authors.lastname: di Magliano
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Heiser
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Nielsen
authors.forename: Drucilla J
authors.initials: DJ
authors.lastname: Roberts
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.forename: Yan Ping
authors.initials: YP
authors.lastname: Qi
authors.forename: Stephan
authors.initials: S
authors.lastname: Gysin
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-del Castillo
authors.forename: Vijay
authors.initials: V
authors.lastname: Yajnik
authors.forename: Bozena
authors.initials: B
authors.lastname: Antoniu
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Warshaw
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014704:Veratrum Alkaloids / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C000541:cyclopamine