Jamieson, T. et al. (2012) Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. Journal of Clinical Investigation, 122(9), pp. 3127-3144. (doi: 10.1172/JCI61067)
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Publisher's URL: http://dx.doi.org/10.1172/JCI61067
Abstract
The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2- activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.
Item Type: | Articles (Other) |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Samuel, Dr Michael and Clarke, Dr Mairi and Huels, Mr David and Nibbs, Professor Rob and Steele, Dr Colin and Jamieson, Mr Thomas and Sansom, Professor Owen and Olson, Professor Michael |
Authors: | Jamieson, T., Clarke, M., Steele, C. W., Samuel, M. S., Neumann, J., Jung, A., Huels, D., Olson, M. F., Das, S., Nibbs, R. J. B., and Sansom, O. J. |
Subjects: | Q Science > Q Science (General) Q Science > QR Microbiology > QR180 Immunology |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
Research Group: | Prof Nibbs |
Journal Name: | Journal of Clinical Investigation |
Journal Abbr.: | J. Clin. Invest. |
Publisher: | American Society for Clinical Investigation |
ISSN: | 0021-9738 |
ISSN (Online): | 1558-8238 |
Published Online: | 27 August 2012 |
Published Online: | 27 August 2012 |
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