• 在自发性结肠癌和结肠炎相关结直肠癌(CAC)的小鼠模型中,巨噬细胞中缺失Gpr35可显著抑制肿瘤生长、减少血管生成;
  • GPR35通过Na/K-ATPase依赖性离子泵和Src活化,促进新生血管生成和基质金属蛋白酶MMP2活性,而用GPR35特异性蛋白肽阻断Gpr35能使CAC小鼠的肿瘤缩小;
  • 携带GPR35T108M突变(增加PSC和UC风险)的巨噬细胞,能分泌更多的血管生成因子IL-8和VEGF以及MMP2,其上清液能诱导人微血管上皮细胞形成小管。
Gut [IF:19.819]

Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment



03-23, Article

Abstract & Authors:展开

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.

First Authors:
Ester Pagano

Correspondence Authors:
Nicole Kaneider

All Authors:
Ester Pagano,Joshua E Elias,Georg Schneditz,Svetlana Saveljeva,Lorraine M Holland,Francesca Borrelli,Tom H Karlsen,Arthur Kaser,Nicole Kaneider