title: Combination of hedgehog signaling blockage and chemotherapy leads to tumor reduction in pancreatic adenocarcinomas.
abstract: OBJECTIVE
  Activation of the hedgehog signal transduction pathway, triggered by hedgehog binding to the transmembrane receptor patched 1 (PTCH1) or by mutations in the PTCH1 gene, plays an important role in the development of various tumors.
  
  
  METHODS
  To investigate whether the Hedgehog signaling pathway is also active in human pancreatic adenocarcinomas, we determined the expression levels of the known Hedgehog target genes PTCH1 and GLI-1 in pancreatic tumors. To determine whether alterations in the PTCH1 gene are responsible for this pathway activation, we screened pancreatic carcinomas for mutations in PTCH. To investigate the contribution of hedgehog signaling to the tumorigenicity of pancreatic tumor cells, we blocked the Hedgehog pathway in cultured tumor cells and xenografts using the steroidal alkaloid cyclopamine and the small-molecule Hedgehog inhibitor Hh-Antag.
  
  
  RESULTS
  We identified single nucleotide polymorphisms (SNPs) within the PTCH1 gene but no somatic PTCH1 mutations. Pathway-blockage resulted in a significant dose-dependent reduction of tumor cell growth in vitro and in vivo. Moreover, combined treatment with cyclopamine and the conventional antimetabolite gemcitabine revealed a synergistic effect on the reduction of tumor growth in pancreatic adenocarcinoma xenografts.
  
  
  CONCLUSIONS
  Inhibition of Hedgehog signaling could be a promising approach for the treatment of pancreatic adenocarcinomas.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany. marcus.bahra@charite.de
authors.forename: Marcus
authors.initials: M
authors.lastname: Bahra
authors.forename: Carsten
authors.initials: C
authors.lastname: Kamphues
authors.forename: Sabine
authors.initials: S
authors.lastname: Boas-Knoop
authors.forename: Steffen
authors.initials: S
authors.lastname: Lippert
authors.forename: Ulrike
authors.initials: U
authors.lastname: Esendik
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Frank
authors.initials: F
authors.lastname: Heppner
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1; D000093542:Gemcitabine
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D003841:Deoxycytidine; C000541:cyclopamine; D000093542:Gemcitabine