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(Chest. 2004;125:133S.)
© 2004 American College of Chest Physicians

The Chemokine Receptor, CXCR2, Mediates the Tumorigenic Effects of ELR+ CXC Chemokines*

Michael P. Keane, MD, FCCP; Marie D. Burdick, BS; Ying Ying Xue, BS; Marin Lutz, BS; John A. Belperio, MD and Robert M. Strieter, MD, FCCP

* From Lung Cancer SPORE at the David Geffen School of Medicine at UCLA, Departments of Medicine (Drs. Keane, Belperio, Ms. Burdick, Ms. Xue, and Ms. Lutz) and Pathology (Dr. Strieter), Division of Pulmonary and Critical Care Medicine, Los Angeles, CA.

Correspondence to: Michael P. Keane, MD, FCCP, Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, 900 Veterans Ave, 14–154 Warren Hall, Los Angeles, CA 90024-1922; e-mail: MPKeane{at}mednet.ucla.edu

ELR+ CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of non-small cell lung cancer (NSCLC)-derived angiogenic activity, and support tumorigenesis in models of human NSCLC growth and metastasis in SCID mice. ELR+ CXC chemokines share a common chemokine receptor, CXCR2, which promotes the angiogenic activity of these chemokines. We hypothesized that CXCR2 in vivo mediates the proangiogenic effects of ELR+ CXC chemokines during tumorigenesis. To test this postulate, we employed a 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 determined that there was a correlation of the expression of endogenous ELR+ CXC chemokines that paralleled tumor growth and metastatic potential of LLC tumors in CXCR2 +/+ mice. Next, we found that LLC primary tumors were significantly reduced in size in CXCR2 –/– mice at 4 weeks. 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 areas of necrosis and reduced vascular density, as compared to tumor grown in CXCR2 +/+ mice. These findings were further confirmed in CXCR2 +/+ mice in the presence of specific neutralizing antibodies 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, and highlights the importance of developing strategies to attenuate CXCR2 biology in NSCLC.


   Footnotes
 
Abbreviations: LLC = Lewis lung carcinoma; NSCLC = non-small cell lung cancer

Supported by grants CA87879, P50CA90388, and P50HL67665.





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