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PPAR Research
Volume 2008 (2008), Article ID 769413, 19 pages
http://dx.doi.org/10.1155/2008/769413
Review Article

CXCR4 in Cancer and Its Regulation by PPARγ

1Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5
2Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1

Received 4 April 2008; Revised 25 June 2008; Accepted 10 July 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Cynthia Lee Richard and Jonathan Blay. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Chemokines are peptide mediators involved in normal development, hematopoietic and immune regulation, wound healing, and inflammation. Among the chemokines is CXCL12, which binds principally to its receptor CXCR4 and regulates leukocyte precursor homing to bone marrow and other sites. This role of CXCL12/CXCR4 is “commandeered” by cancer cells to facilitate the spread of CXCR4-bearing tumor cells to tissues with high CXCL12 concentrations. High CXCR4 expression by cancer cells predisposes to aggressive spread and metastasis and ultimately to poor patient outcomes. As well as being useful as a marker for disease progression, CXCR4 is a potential target for anticancer therapies. It is possible to interfere directly with the CXCL12:CXCR4 axis using peptide or small-molecular-weight antagonists. A further opportunity is offered by promoting strategies that downregulate CXCR4 pathways: CXCR4 expression in the tumor microenvironment is modulated by factors such as hypoxia, nucleosides, and eicosanoids. Another promising approach is through targeting PPAR to suppress CXCR4 expression. Endogenous PPAR 𝛾 such as 15-deoxy- Δ 1 2 , 1 4 -PG J 2 and synthetic agonists such as the thiazolidinediones both cause downregulation of CXCR4 mRNA and receptor. Adjuvant therapy using PPAR 𝛾 agonists may, by stimulating PPAR 𝛾 -dependent downregulation of CXCR4 on cancer cells, slow the rate of metastasis and impact beneficially on disease progression.