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 PPARγ such as 15-deoxy-Δ12,14-PGJ2 and synthetic agonists such as the thiazolidinediones both cause downregulation of CXCR4 mRNA and receptor. Adjuvant therapy using PPARγ agonists may, by stimulating PPARγ-dependent downregulation of CXCR4 on cancer cells, slow the rate of metastasis and impact beneficially on disease progression.
Highlights
The regulation of the distribution of motile cells in both normal and disease situations depends upon a variety of peptide and nonpeptide mediators, which stimulate cell movement by both directed and nondirected mechanisms
This review describes the roles of CXCL12 and CXCR4 in normal tissue functions and in cancer, and suggests that the regulation of CXCR4 expression by peroxisome proliferator-activated receptor γ (PPARγ) may emerge to be a unique avenue by which a key receptor involved in cancer cell metastasis can be suppressed in a way that will assist with disease therapy
Shioppa and colleagues found that hypoxia increased CXCR4 mRNA and cell-surface protein expression in several cell types, including monocytes, human monocyte-derived macrophages, tumor-associated macrophages, human umbilical vein endothelial cells (HUVECs), CAOV3 ovarian carcinoma cells, and MCF-7 breast carcinoma cells, leading to increased migration towards CXCL12 due to the activation of hypoxia-inducible factor-1 (HIF-1) [132]
Summary
The regulation of the distribution of motile cells in both normal and disease situations depends upon a variety of peptide and nonpeptide mediators, which stimulate cell movement by both directed (chemotaxis) and nondirected (chemokinesis) mechanisms. Amongst these mediators are the chemokines, a class of peptide mediators that play critical roles in normal development, regulation of the hematopoietic and immune systems in the adult, and in repair processes such as wound healing and inflammation. This review describes the roles of CXCL12 and CXCR4 in normal tissue functions and in cancer, and suggests that the regulation of CXCR4 expression by PPARγ may emerge to be a unique avenue by which a key receptor involved in cancer cell metastasis can be suppressed in a way that will assist with disease therapy
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