Please use this identifier to cite or link to this item:
Scopus Web of Science® Altmetric
Type: Journal article
Title: Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis
Author: Jamieson, T.
Clarke, M.
Steele, C.
Samuel, M.
Neumann, J.
Jung, A.
Huels, D.
Olson, M.
Das, S.
Nibbs, R.
Sansom, O.
Citation: Journal of Clinical Investigation, 2012; 122(9):3127-3144
Publisher: Amer Soc Clinical Investigation Inc
Issue Date: 2012
ISSN: 0021-9738
Statement of
Thomas Jamieson, Mairi Clarke, Colin W. Steele, Michael S. Samuel, Jens Neumann, Andreas Jung, David Huels, Michael F. Olson, Sudipto Das, Robert J.B. Nibbs, and Owen J. Sansom
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.
Keywords: Neutrophils
Animals, Inbred Strains
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Colonic Neoplasms
Skin Neoplasms
Cell Transformation, Neoplastic
Precancerous Conditions
Dermatitis, Contact
Tetradecanoylphorbol Acetate
Dextran Sulfate
Receptors, Interleukin-8B
Chemokines, CXC
Tumor Burden
Statistics, Nonparametric
Gene Expression
Mice, 129 Strain
Rights: Copyright © 2012, American Society for Clinical Investigation
DOI: 10.1172/JCI61067
Published version:
Appears in Collections:Aurora harvest 4
Molecular and Biomedical Science publications

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.