Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

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Involvement of chemokine receptors in breast cancer metastasis.

Chemokines: A New Classification System and Their Role in Immunity

During the last five years, the development of bioinformatics and EST databases has been primarily responsible for the identification of many new chemokines and chemokine receptors. The chemokine field has also received considerable attention since chemokine receptors were found to act as co-receptors for HIV infection (1). In addition, chemokines, along with adhesion molecules, are crucial during inflammatory responses for a timely recruitment of specific leukocyte subpopulations to sites of tissue damage. However, chemokines and their receptors are also important in dendritic cell maturation (2), B (3), and T (4) cell development, Th1 and Th2 responses, infections, angiogenesis, and tumor growth as well as metastasis (5). Furthermore, an increase in the number of chemokine/receptor transgenic and knock-out mice has helped to define the functions of chemokines in vivo. In this review we discuss some of the chemokines' biological effects in vivo and in vitro, described in the last few years, and the implications of these findings when considering chemokine receptors as therapeutic targets.

The biology of chemokines and their receptors.

Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors

In this review, the authors discuss the properties of chemokines and their receptors and highlight the roles of these chemoattractants in selected clinical disorders.

The Many Roles of Chemokines and Chemokine Receptors in Inflammation

Vascularization of organs generally occurs by remodelling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required by early vascular systems, many of which are receptor tyrosine kinases and their ligands, have been defined by analysis of mutant mice. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis have not been identified. The cell-surface receptor CXCR4 is a seven-transmembrane-spanning, G-protein-coupled receptor for the CXC chemokine PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stromal-cell-derived factor), which is responsible for B-cell lymphopoiesis, bone-marrow myelopoiesis and cardiac ventricular septum formation. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1. Here we report that CXCR4 is expressed in developing vascular endothelial cells, and that mice lacking CXCR4 or PBSF/SDF-1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, haematopoiesis and cardiogenesis, like mice lacking PBSF/SDF-1, indicating that CXCR4 is a primary physiological receptor for PBSF/SDF-1. We conclude that PBSF/SDF-1 and CXCR4 define a new signalling system for organ vascularization.

The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.

Publisher Summary Most members of chemokines are reported to be chemotactic for leukocytes and are produced in response to proinflaminatory agents and designated as inducible inflammatory mediators that dictate leukocyte activation and chemotaxis to the site of inflammation. Gene targeting studies reveal that MIP-lα is required for the pathogenesis of coxackievirus-induced myocarditis and influenza virus-induced pneumonitis. However, some chemokines are thought to have additional functions, including hematopoiesis and angiogenesis. MIP-lα is reported to inhibit the growth of hematopoietic stem cells in vitro . From its initial discovery, the importance of SDF-l/PBSF and CXCR4 has grown to cover a variety of biological and pathological functions. It was exciting that a chemokine is crucial for the development including hematopoietic precursors in addition to cell adhesion molecules. Finally, the discovery about the involvement of CXCR4 in HIV-1 infection raised the possibilities that therapy could be aimed at blocking CXCR4 using peptides or other agents or at regulating the expression of CXCR4 or SDF-l/PBSF. There is no doubt that further understanding of the biological and pathological properties of SDF-1/ PBSF and CXCR4 should be pursued.

Kenji Kawabata

Papers

The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.

A CXC chemokine SDF-1/PBSF: a ligand for a HIV coreceptor, CXCR4.