CXCR4 in Cancer and Its Regulation by PPARgamma

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 PPARgamma such as 15-deoxy-Delta(12,14)-PGJ(2) and synthetic agonists such as the thiazolidinediones both cause downregulation of CXCR4 mRNA and receptor. Adjuvant therapy using PPARgamma agonists may, by stimulating PPARgamma-dependent downregulation of CXCR4 on cancer cells, slow the rate of metastasis and impact beneficially on disease progression.

Figure 1

Production of PGD₂ and conversion to its metabolites. Prostanoids follow an initial common pathway in which arachidonic acid is released from membrane phospholipids by phospholipase A₂ and then converted to the short-term intermediates PGG₂ and PGH₂ by cyclooxygenases. Prostaglandin D synthase forms PGD₂ itself, but subsequent nonenzymatic reactions in aqueous media lead to the sequential production of prostaglandin J₂ (PGJ₂), 9-deoxy-Δ⁹,Δ^12‐13,14-dihydro-PGD₂ (Δ¹²‐PGJ₂), and 15-deoxy-Δ^12,14‐PGJ₂ (15dPGJ₂).

Figure 2

Time course of changes in cell-surface CXCR4 protein expression on HT-29 cells by PGD₂ and its metabolites. HT-29 cells were treated with vehicle or with 10 μM PGD₂ (light gray bars), 10 μM PGJ₂ (dark gray bars), or 3 μM 15dPGJ₂ (hatched bars), and cell-surface CXCR4 protein expression was measured at the indicated time points. The data shown are expressed relative to the level of CXCR4 receptor on cells treated with vehicle alone at that time point. Values have also been corrected for any possible changes in cell number. The data are mean values ± SE (n = 4). Significant decrease due to prostaglandin, **P < .01;*P < .05. The figure is taken from [204] with permission.

Figure 3

How PPARγ downregulation of CXCR4 may act to decrease metastasis. Tumor cells typically have high levels of CXCR4 at their cell surface. During metastasis, cancer cells that find their way into the bloodstream lodge in tissues that have high concentrations of CXCL12 (e.g., lungs, liver, and bone marrow). CXCL12 both encourages the entry of cells into the tissue and promotes growth of the cell population. Downregulation of CXCR4 by PPARγ activation (endogenous 15dPGJ₂ or thiazolidinedione drugs, TZDs) will interfere with this process and may impede metastasis.