期刊
GASTROENTEROLOGY
卷 144, 期 1, 页码 134-U256出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2012.09.061
关键词
GIST Mouse Model; Ptch Mutation; Active Hh Cascade; Pdgfr alpha Signaling Cascade
资金
- Wilhelm-Sander-Stiftung [2003.112.3]
- Deutsche Krebshilfe (KoSAR) [109837]
- Deutsche Forschungsgemeinschaft [HA2197/7-1]
- Austrian Science Fund (FWF) [P20652]
- Austrian Genome Project GEN-AU (MedSys)
- priority program Biosciences and Health of the University of Salzburg
- NATIONAL CANCER INSTITUTE [P50CA140146] Funding Source: NIH RePORTER
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 Pdgfr alpha, but not Kit, was overexpressed and activated. Lineage tracing revealed that Cre-expressing intestinal cells were Kit-negative. These cells sometimes expressed Pdgfr alpha 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 Pdgfr alpha, but not Kit. Activation of Pdgfr alpha signaling appears to facilitate tumorigenesis.
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