Inactivation of Patched1 in Mice Leads to Development of Gastrointestinal Stromal-Like Tumors That Express Pdgfrα but Not Kit

Gastroenterology. 2013 Jan;144(1):134-144.e6. doi: 10.1053/j.gastro.2012.09.061. Epub 2012 Oct 3.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Gastrointestinal Neoplasms / drug therapy
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Neoplasms / metabolism
  • Gastrointestinal Neoplasms / pathology
  • Gastrointestinal Stromal Tumors / drug therapy
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / metabolism*
  • Gastrointestinal Stromal Tumors / pathology
  • Gene Expression
  • Genotype
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Humans
  • Imatinib Mesylate
  • Integrases / genetics
  • Integrases / metabolism
  • Intestinal Mucosa / metabolism
  • Kruppel-Like Transcription Factors / metabolism
  • Leiomyosarcoma / genetics*
  • Leiomyosarcoma / metabolism
  • Mice
  • Muramidase / genetics
  • Muramidase / metabolism
  • Nerve Tissue Proteins / metabolism
  • Patched Receptors
  • Patched-1 Receptor
  • Piperazines / therapeutic use
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Pyrimidines / therapeutic use
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / genetics
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3

Substances

  • Benzamides
  • Gli1 protein, mouse
  • Gli2 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Piperazines
  • Protein Kinase Inhibitors
  • Ptch1 protein, mouse
  • Pyrimidines
  • Receptors, Cell Surface
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha
  • Cre recombinase
  • Integrases
  • Muramidase
  • lysozyme M, mouse