Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

• Published in: Gut 2022-03, Vol.71 (3), p.509-520
• Main Authors: Pagano, Ester, Elias, Joshua E, Schneditz, Georg, Saveljeva, Svetlana, Holland, Lorraine M, Borrelli, Francesca, Karlsen, Tom H, Kaser, Arthur, Kaneider, Nicole C
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Cancer therapies; Cell proliferation; Cholangitis; Cholangitis, Sclerosing - genetics; Cholangitis, Sclerosing - pathology; Colitis, Ulcerative - genetics; Colitis, Ulcerative - pathology; Colon cancer; Colonic Neoplasms - etiology; Colonic Neoplasms - pathology; Colorectal cancer; Cytokines; Disease Models, Animal; Epithelial cells; GI cancer; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Kinases; Liver cancer; Macrophages; Macrophages - physiology; Matrix metalloproteinase; Medical prognosis; Metalloproteinase; Mice; Microenvironments; Mutation; Na+/K+-exchanging ATPase; Neovascularization, Pathologic - etiology; Neutrophils; Phosphorylation; Pluripotency; Polyposis coli; Potassium; primary sclerosing cholangitis; receptor characterisation; Receptors, G-Protein-Coupled - physiology; Signal transduction; Stem cells; Tumor Microenvironment; Tumor suppressor genes; Tumors; Ulcerative colitis
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2020-323363

ObjectivePrimary 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.DesignMice 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.ResultsHere, 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.ConclusionsActivation 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.