Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis

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)

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)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nibbs, Professor Robert and Steele, Dr Colin and Clarke, Dr Mairi and Huels, Mr David and Samuel, Dr Michael and Sansom, Professor Owen and Olson, Professor Michael and Jamieson, Mr Thomas
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 > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
519821An investigation of the pro-tumorigenic activity of the chemokine receptor CXCR2 using models of de novo tumorigenesis.Robert NibbsMedical Research Council (MRC)G0900992III -IMMUNOLOGY