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GI cancer
Original research
Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment
  1. Ester Pagano1,2,
  2. Joshua E Elias1,3,
  3. Georg Schneditz1,4,
  4. Svetlana Saveljeva1,
  5. Lorraine M Holland1,
  6. Francesca Borrelli2,
  7. Tom H Karlsen4,
  8. Arthur Kaser1,3,
  9. Nicole C Kaneider1,3
  1. 1 Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
  2. 2 Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
  3. 3 Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
  4. 4 Norwegian PSC Research Center, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  1. Correspondence to Dr Nicole C Kaneider, Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 1TN, UK; nk428{at}cam.ac.uk

Abstract

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.

  • colorectal cancer
  • primary sclerosing cholangitis
  • angiogenesis
  • ulcerative colitis
  • receptor characterisation

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. All data relevant to the study are included in the article or uploaded as online supplemental information. n/a.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/gutjnl-2020-323363

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    Data availability statement

    Data sharing not applicable as no datasets generated and/or analysed for this study. All data relevant to the study are included in the article or uploaded as online supplemental information. n/a.

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    Footnotes

    • Twitter @ester.pagano, @tomhemmingk

    • Correction notice This article has been corrected since it published Online First. The author, Dr Kaneider's, name has been updated.

    • Contributors Conceptualisation: NK and AK. Methology: NK, EP, GS, JEE and SS. Validation: NK, GS, JEE and EP. Formal analysis: NK and EP. Investigation: NK, GS, JEE, EP and LMH. Resources: LMH. Writing—original Draft. NK and AK, visualisation: NK and GS. Supervision: NK, AK and THK. Funding Acquisition: NK, AK and THK. External mentor: FB to EP.

    • Funding This paper was supported by the Wellcome Trust (Clinical Research Career Development Fellowship to NK 216630/Z/19/Z, Career Re-entry Fellowship to NK 103077/Z/13/Z, Senior Investigator Award 106260/Z/14/Z to AK, PhD training fellowship for clinicians UNS59491 to JEE), the European Research Council under the European Community’s Seventh Framework Programme Consolidator Grant no 648 889 to AK, and Scientia Fellowship (FP7-PEOPLE-2013-COFUND) grant agreement no 609 020 to GS, the Addenbrooke’s Charitable Trust (ACT 25/16A) to JEE, and an UniNA and Compagnia Di San Paolo ‘STAR programme for young researchers’ fellowship to EP. This work was further supported by the NIHR Cambridge BRC. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.