The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases.
ABSTRACT Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the CXCL12-CXCR4 biological axis is important in mediating non-small cell lung cancer metastases. Our results indicate that both non-small cell lung cancer tumor specimens resected from patients and non-small cell lung cancer cell lines express CXCR4, but not CXCL12. Non-small cell lung cancer cell lines undergo chemotaxis in response to CXCL12. CXCL12-CXCR4 activation of non-small cell lung cancer cell lines showed intracellular calcium mobilization and mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-1/2 phosphorylation without change in either proliferation or apoptosis. Target organs in a murine model that are the preferred destination of human non-small cell lung cancer metastases elaborate higher levels of CXCL12 than does the primary tumor, and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient mice expressing human non-small cell lung cancer abrogated organ metastases, without affecting primary tumor-derived angiogenesis. These data suggest that the CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer.
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Article: CXC chemokines in angiogenesis.[show abstract] [hide abstract]
ABSTRACT: CXC chemokines display pleiotropic effects in immunity, regulating angiogenesis, and mediating organ-specific metastases of cancer. In the context of angiogenesis, CXC chemokines are a unique family of cytokines, known for their ability to behave in a disparate manner in the regulation of angiogenesis. Members that contain the 'ELR' motif are potent promoters of angiogenesis, and mediate their angiogenic activity via binding and activating CXCR2 on endothelium. In contrast, members, in general, those are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis, and bind to CXCR3 on endothelium. This review will discuss the biology of these angiogenic and angiostatic CXC chemokines and discuss their disparate angiogenic activity in the context of a variety of disorders.Cytokine & Growth Factor Reviews 01/2006; 16(6):593-609. · 8.83 Impact Factor
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ABSTRACT: The family of MAP-kinases include ERKs, p38 MAP-kinases and JNKs. Recently, the role of MAP-kinases in T lymphocytes has attracted particular interest. Genetically modified mouse models have brought insight into the specific function of each MAP-kinase pathway in T lymphocyte biology. Studies clearly show that these pathways are not redundant and that the role of each pathway depends on the T cell type and differentiation stage.Current Opinion in Immunology 07/2001; · 8.77 Impact Factor
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ABSTRACT: Leukocytes migrate from the blood to sites of inflammation in response to locally produced chemoattractants that activate specific cell surface receptors. The primary structures of leukocyte receptors for N-formyl peptides, C5a, platelet-activating factor, and 8 of the 18 known human chemokines (interleukin-8 and related molecules) have been deduced from cloned cDNAs. All of these are seven-transmembrane-domain rhodopsin-like G protein-coupled receptors. Biochemical and molecular genetic analysis of the chemoattractant receptors indicates that the chemoattractants may have both broadly overlapping as well as specialized roles in the regulation of acute and chronic inflammation. Interestingly, the chemokine receptors have functional homologues in human cytomegalovirus and Herpesvirus saimiri. Moreover, the Duffy antigen, which mediates invasion of erythrocytes by Plasmodium vivax, a major cause of malaria, is also a chemokine binding protein. These surprising developments suggest that in addition to leukocyte-mediated inflammation, the chemokines may also be involved in erythrocyte function and, through molecular mimicry, in microbial pathogenesis.Annual Review of Immunology 02/1994; 12:593-633. · 36.56 Impact Factor