CXC chemokines in angiogenesis and metastasis.

CS11-03 Over the last 20 years, the biology of chemokines has expanded beyond their initial role in mediating migration of specific subsets of leukocytes. More specifically, CXC Chemokines demonstrate pleiotropic effects in the pathobiology of a variety of cancers. CXC chemokines enhance innate and adaptive immunity, regulate angiogenesis, and mediate tumor cell metastases. For example, the CXC chemokine receptor, CXCR2, and its putative CXCR2 ligands (i.e., CXCL1/GROα, CXCL5/ENA-78, and IL-8/CXCL8) have been determined to promote angiogenesis in a variety of solid tumors. In contrast, the CXC chemokine receptor, CXCR3, and its putative CXCR3 ligands (i.e., CXCL9, CXCL10, and CXCL11) behave as both potent promoters of Th1 cytokine-dependent cell-mediated immunity and inhibit angiogenesis via the concept of For example, first 9priming9 the circulating pool of mononuclear cells to express CXCR3 can optimize immunoangiostasis. Once systemic CXCR3 levels are optimally expressed on mononuclear cells, induction of intratumor CXCR3 ligand production optimizes the chemotactic gradient necessary to target circulating CXCR3+ mononuclear cells to the tumor and concomitantly inhibit angiogenesis. The combined temporal and spatial priming and induction optimizes both tumor immunity and inhibition of angiogenesis. The tumor microenvironment and receptor signaling within the tumor cell plays a role in promoting the expression of hypoxia-responsive genes that may be relevant in promoting tumor metastases. The CXC chemokine, CXCL12, and its receptor, CXCR4 promote metastases of a variety of solid tumors. Recent findings have linked HIF-1α and the expression of CXCR4 on tumor cells, and the expression of CXCR4 on these cells may represent a biomarker that predicts the metastatic potential of specific tumor cells. In this presentation, we will review the importance of CXC chemokines in regulating angiogenesis and metastases; and demonstrate why they should be seen as important therapeutic targets for intervention in cancer.