Erratum: Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Abstract A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.

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Faculty Opinions recommendation of A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1052684.536672 ◽

2007 ◽

Author(s):

Albert Deisseroth

Keyword(s):

Colon Cancer ◽

Cancer Cell ◽

Tumour Growth ◽

Human Colon ◽

Colon Cancer Cell ◽

Human Colon Cancer Cell ◽

Human Colon Cancer ◽

Immunodeficient Mice

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Faculty Opinions recommendation of A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1052684.14741250 ◽

2011 ◽

Author(s):

Saghi Ghaffari

Keyword(s):

Colon Cancer ◽

Cancer Cell ◽

Tumour Growth ◽

Human Colon ◽

Colon Cancer Cell ◽

Human Colon Cancer Cell ◽

Human Colon Cancer ◽

Immunodeficient Mice

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Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Gut ◽

10.1136/gutjnl-2020-323363 ◽

2021 ◽

pp. gutjnl-2020-323363

Author(s):

Ester Pagano ◽

Joshua E Elias ◽

Georg Schneditz ◽

Svetlana Saveljeva ◽

Lorraine M Holland ◽

...

Keyword(s):

Colon Cancer ◽

Tumour Growth ◽

Tumour Microenvironment ◽

Tube Formation ◽

Tissue Remodelling ◽

Colon Cancers ◽

Inflammatory Bowel ◽

Ion Pumping ◽

G Protein Coupled

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.

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