Abstract
The Glu-Leu-Arg(+) (ELR(+)) CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of nonsmall cell lung cancer-derived angiogenic activity and support tumorigenesis. ELR(+) CXC chemokines share a common chemokine receptor, CXCR2. We hypothesized that CXCR2 mediates the proangiogenic effects of ELR(+) CXC chemokines during tumorigenesis. To test this postulate, we used syngeneic murine Lewis lung cancer (LLC; 3LL, H-2(b)) heterotopic and orthotopic tumor model systems in C57BL/6 mice replete (CXCR2(+/+)) and deficient in CXCR2 (CXCR2(-/-)). We first demonstrated a correlation of the expression of endogenous ELR(+) CXC chemokines with tumor growth and metastatic potential of LLC tumors. Next, we found that LLC primary tumors were significantly reduced in growth in CXCR2(-/-) mice. Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2(-/-) mice. Morphometric analysis of the primary tumors in CXCR2(-/-) mice demonstrated increased necrosis and reduced vascular density. These findings were further confirmed in CXCR2(+/+) mice using specific neutralizing Abs to CXCR2. The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR(+) CXC chemokines in a preclinical model of lung cancer.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Carcinoma, Lewis Lung / blood supply
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Carcinoma, Lewis Lung / pathology
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Carcinoma, Lewis Lung / prevention & control*
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Carcinoma, Lewis Lung / secondary
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Carcinoma, Non-Small-Cell Lung / blood supply
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Non-Small-Cell Lung / prevention & control*
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Carcinoma, Non-Small-Cell Lung / secondary
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Cell Division / genetics
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Cell Division / immunology
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Cell Movement / genetics
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Cell Movement / immunology
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Chemokine CXCL1
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Chemokines, CXC / biosynthesis
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Disease Models, Animal
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Endothelium, Vascular / immunology
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Endothelium, Vascular / metabolism
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Lung Neoplasms / blood supply
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Lung Neoplasms / pathology
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Lung Neoplasms / prevention & control*
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Lung Neoplasms / secondary
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Sequence Data
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Necrosis
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Neoplasm Transplantation / methods
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Neovascularization, Pathologic / immunology*
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / prevention & control*
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Receptors, CXCR3
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Receptors, Chemokine / biosynthesis
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Receptors, Chemokine / physiology
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Receptors, Interleukin-8B / biosynthesis
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Receptors, Interleukin-8B / deficiency*
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Receptors, Interleukin-8B / genetics*
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Receptors, Interleukin-8B / physiology
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Transplantation, Heterotopic / immunology
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Transplantation, Heterotopic / pathology
Substances
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Chemokine CXCL1
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Chemokines, CXC
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Cxcl1 protein, mouse
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Cxcr3 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Receptors, CXCR3
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Receptors, Chemokine
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Receptors, Interleukin-8B