Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment.

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Pagano, Ester 
Elias, Joshua E 
Schneditz, Georg 
Saveljeva, Svetlana 
Holland, Lorraine M 

OBJECTIVE: Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers. DESIGN: Mice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays. RESULTS: Here, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors. CONCLUSIONS: Activation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages' ability to create a tumour-permissive environment.

angiogenesis, colorectal cancer, primary sclerosing cholangitis, receptor characterisation, ulcerative colitis, Animals, Cholangitis, Sclerosing, Colitis, Ulcerative, Colonic Neoplasms, Disease Models, Animal, Macrophages, Mice, Neovascularization, Pathologic, Receptors, G-Protein-Coupled, Tumor Microenvironment
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Wellcome Trust (216630/Z/19/Z)
Wellcome Trust (103077/Z/13/Z)
Wellcome Trust (106260/Z/14/Z)
European Research Council (648889)
BRC pump priming award to NCK