title: Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit.
abstract: OBJECTIVE
  A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the cellular origin of GIST. Little also is known about why Hedgehog (HH) signaling is activated in some GIST. HH binds to and inactivates the receptor protein patched homolog (PTCH).
  
  
  METHODS
  Ptch was conditionally inactivated in mice (to achieve constitutive HH signaling) using a Cre recombinase regulated by the lysozyme M promoter. Cre-expressing cells were traced using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, immunoblot, and quantitative reverse-transcriptase polymerase chain reaction analyses. Cell transformation was assessed by soft agar assay.
  
  
  RESULTS
  Loss of Ptch from lysozyme M-expressing cells resulted in the development of tumors of GIST-like localization and histology; these were reduced when mice were given imatinib, a drug that targets KIT and PDGFRA. The Hh signaling pathway was activated in the tumor cells, and Pdgfrα, but not Kit, was overexpressed and activated. Lineage tracing revealed that Cre-expressing intestinal cells were Kit-negative. These cells sometimes expressed Pdgfrα and were located near Kit-positive interstitial cells of Cajal. In contrast to KIT, activation of PDGFRA increased anchorage-independent proliferation and was required for tumor formation in mice by cells with activated HH signaling.
  
  
  CONCLUSIONS
  Inactivation of Ptch in mice leads to formation of GIST-like tumors that express Pdgfrα, but not Kit. Activation of Pdgfrα signaling appears to facilitate tumorigenesis.
authors.affiliation: Department of Human Genetics, University Medical Center, Göttingen, Germany.
authors.forename: Penelope
authors.initials: P
authors.lastname: Pelczar
authors.forename: Arne
authors.initials: A
authors.lastname: Zibat
authors.forename: Willemijn A
authors.initials: WA
authors.lastname: van Dop
authors.forename: Jarom
authors.initials: J
authors.lastname: Heijmans
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gruber
authors.forename: Frauke
authors.initials: F
authors.lastname: Nitzki
authors.forename: Anja
authors.initials: A
authors.lastname: Uhmann
authors.forename: Maria V
authors.initials: MV
authors.lastname: Guijarro
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Walter
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
mesh_terms: D000818:Animals; D001549:Benzamides; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D007890:Leiomyosarcoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009113:Muramidase / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: D001549:Benzamides; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C000606240:Ptch1 protein, mouse; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C045073:Cre recombinase; D019426:Integrases; D009113:Muramidase; C472450:lysozyme M, mouse