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

Abstract

Background and aims A fraction of gastrointestinal stromal tumors (GIST) overexpress PDGFRA rather than KIT. Presently it is unknown if this reflects a complementary oncogenic potential of PDGFRA and KIT pathways, or heterogeneity in the cellular origin of GIST. Similarly unknown is the significance of activated Hedgehog (HH)/PATCHED1 (PTCH) signaling found in many GIST. Methods Mouse Ptch was conditionally inactivated using a Cre recombinase driven by the lysozyme M (LysM) promoter. Lineage tracing was done using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, Western blot and qRT-PCR. Cellular transformation was assessed by clonogenic assay. Results Inactivation of Ptch in LysM-expressing cells resulted in imatinib-responsive tumors of GIST-like localization and histology. In addition to activation of Hh signaling, the tumors showed overexpression and activation of Pdgfrα, but not of Kit. Lineage tracing revealed that LysM-expressing intestinal cells were Kit-negative. These cells were juxtapposed with Kit-positive interstitial cells of Cajal (ICC) and sometimes co-expressed Pdgfrα. In contrast to KIT, PDGFRA cooperated with HH signaling in cellular transformation. Conclusions Mutations in Ptch result in formation of Pdgfrα-positive Kit-negative GIST-like tumors in mice. These tumors may develop due to cooperativity between Hh and Pdgfrα pathways from Kit-negative cells in the intestine.

Role of anoctamins in cancer and apoptosis

“…Hh and Wnt signalling frequently act together in controlling cell growth and tissue morphogenesis. Hh is also active in 'embryonic cancers' such as basal cell carcinoma of the skin, stromal cancer [45,46] and also during epithelial to mesenchymal transition. Hh expression has been shown to be upregulated in the neoplastic or inflammatory intestine when stem cells compensate for epithelial damage, while suppression rstb.royalsocietypublishing.org Phil.…”

Targeting Disease Persistence in Gastrointestinal Stromal Tumors

“…However, the relationship of KIT 2 ANO1 2 GIST to the ICC lineage cannot be ascertained based on immunohistochemical criteria. A subset of these tumors have been proposed to arise, possibly due to activated hedgehog signaling [18], from interstitial cells expressing platelet-derived growth factor a (PDGFRA); these cells mediate purinergic inhibitory neuromuscular neurotransmission [9]. The majority of GISTs arise on the basis of mutually exclusive, most often heterozygous activating mutations in KIT (75%-80%) [6] or PDGFRA (,10%) [19], which encodes a closely related RTK often coexpressed with KIT [20,21].…”

Regulation of fibroblast lipid storage and myofibroblast phenotypes during alveolar septation in mice

“…PLATELET-DERIVED GROWTH FACTOR receptor-␣ (pdgfr␣)-expressing cells are required for development of the lung, central nervous system, and heart and contribute to malignancies in the gastrointestinal tract, brain, and bone marrow (5,7,13,26,43,52). PDGFR␣ resides in cells which assume divergent characteristics in the brain [oligodendrocyte precursors (OPC)], the heart (epicardial fibroblasts), stromal vascular cells in skeletal muscle, adipocytes in white or brown fat, and stellate cells in the liver (3,18,42,50).…”