Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer

MP Keane, JA Belperio, YY Xue… - The Journal of …, 2004 - journals.aai.org
MP Keane, JA Belperio, YY Xue, MD Burdick, RM Strieter
The Journal of Immunology, 2004journals.aai.org
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 …
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.
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