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Published ahead of print on March 5, 2003, doi:10.1164/rccm.200301-071OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 12, June 2003, 1676-1686

A more recent version of this article appeared on June 15, 2003
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Submitted on January 21, 2003
Accepted on February 17, 2003

The SDF-1/CXCL12/CXCR4 Biological Axis in Non-Small Cell Lung Cancer Metastases

Roderick J Phillips1, Marie D Burdick1, Marin Lutz1, John A Belperio1, Michael P Keane1, and Robert M Strieter2*

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA, 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA; Division of Pulmonary and Critical Care Medicine, Department of Pathology, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA

* To whom correspondence should be addressed. E-mail: rstrieter{at}mednet.ucla.edu.

Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although recent evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that 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 MAP-kinase activation with enhanced ERK 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 the primary tumor, and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to SCID 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.
Key words: chemokines, chemotaxis, lung cancer metastases




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