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The Journal of Immunology, 2004, 172: 2853-2860.
Copyright © 2004 by The American Association of Immunologists

Depletion of CXCR2 Inhibits Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer1

Michael P. Keane*, John A. Belperio*, Ying Y. Xue*, Marie D. Burdick* and Robert M. Strieter2,*,{dagger}

* Division of Pulmonary and Critical Care Medicine and {dagger} Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90024

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-2b) 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.




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