Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/77376
Citations | ||
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 1558-8238 |
Statement of Responsibility: | 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 Animals, Inbred Strains Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice Adenoma Adenocarcinoma Papilloma Colonic Neoplasms Skin Neoplasms Cell Transformation, Neoplastic Precancerous Conditions Colitis Dermatitis, Contact Azoxymethane Tetradecanoylphorbol Acetate 9,10-Dimethyl-1,2-benzanthracene Peroxidase 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: | http://dx.doi.org/10.1172/jci61067 |
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.