ArticleGastroenterology2013
Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit.
Article in Gastroenterology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 34 citations in OpenAlex.
- Hedgehog and Platelet-derived Growth Factor Signaling Intersect during Postnatal Lung Development.American journal of respiratory cell and molecular biology · 2023Article
- Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers.Molecular cancer · 2023Review
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- Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors.Advanced materials (Deerfield Beach, Fla.) · 2020Article
- Hedgehog signalling pathway activation in gastrointestinal stromal tumours is mediated by primary cilia.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2020Article
- Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer.Frontiers in oncology · 2020Review
- Identifying Secondary Mutations in Chinese Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs) by Next Generation Sequencing (NGS).Pathology oncology research : POR · 2020Article
- A 4-month-old boy with gastrointestinal stromal tumor of mesocolon.Cancer biology & therapy · 2019Article
- Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.Oncotarget · 2016Article
- AKT1 Activation is Obligatory for Spontaneous BCC Tumor Growth in a Murine Model that Mimics Some Features of Basal Cell Nevus Syndrome.Cancer prevention research (Philadelphia, Pa.) · 2016Article
- Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth.Nature communications · 2016Article
- Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma.The Journal of pathology · 2016Article
- Article
- Article
- Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.Oncogene · 2015Article
- Review
- Targeting Disease Persistence in Gastrointestinal Stromal Tumors.Stem cells translational medicine · 2015Article
- The Hedgehog pathway: role in cell differentiation, polarity and proliferation.Archives of toxicology · 2015Review
- Regulation of fibroblast lipid storage and myofibroblast phenotypes during alveolar septation in mice.American journal of physiology. Lung cellular and molecular physiology · 2014Article
- Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.Seminars in cell & developmental biology · 2014Review
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Authors and funding
24 authors at 9 institutions in 5 countries.
Funding
Abstract
BACKGROUND &
aimsA 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).
methodsPtch 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.
resultsLoss 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.
conclusionsInactivation 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.
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