This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200301-071OCv1 167/12/1676    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phillips, R. J. Articles by Strieter, R. M. Search for Related Content PubMed PubMed Citation Articles by Phillips, R. J. Articles by Strieter, R. M.

The Stromal Derived Factor–1/CXCL12–CXC Chemokine Receptor 4 Biological Axis in Non–Small Cell Lung Cancer Metastases

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Pathology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California

Correspondence and requests for reprints should be addressed to Robert M. Strieter, M.D., Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, 900 Veteran Ave., 14-154 Warren Hall, Los Angeles, CA 90024. 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 evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the 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 mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-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 does the primary tumor, and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient 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

This article has been cited by other articles:

				M. Yamamoto, H. Kikuchi, M. Ohta, T. Kawabata, Y. Hiramatsu, K. Kondo, M. Baba, K. Kamiya, T. Tanaka, M. Kitagawa, et al. TSU68 Prevents Liver Metastasis of Colon Cancer Xenografts by Modulating the Premetastatic Niche Cancer Res., December 1, 2008; 68(23): 9754 - 9762. [Abstract] [Full Text] [PDF]

				X. He, L. Fang, J. Wang, Y. Yi, S. Zhang, and X. Xie Bryostatin-5 Blocks Stromal Cell-Derived Factor-1 Induced Chemotaxis via Desensitization and Down-regulation of Cell Surface CXCR4 Receptors Cancer Res., November 1, 2008; 68(21): 8678 - 8686. [Abstract] [Full Text] [PDF]

				R M Thomas, J Kim, M P Revelo-Penafiel, R Angel, D W Dawson, and A M Lowy The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia Gut, November 1, 2008; 57(11): 1555 - 1560. [Abstract] [Full Text] [PDF]

				E. C. Keeley, B. Mehrad, and R. M. Strieter Chemokines as Mediators of Neovascularization Arterioscler. Thromb. Vasc. Biol., November 1, 2008; 28(11): 1928 - 1936. [Abstract] [Full Text] [PDF]

				P. L. Wagner, T.-A. Moo, N. Arora, Y.-F. Liu, R. Zarnegar, T. Scognamiglio, and T. J. Fahey III The Chemokine Receptors CXCR4 and CCR7 are Associated with Tumor Size and Pathologic Indicators of Tumor Aggressiveness in Papillary Thyroid Carcinoma Ann. Surg. Oncol., October 1, 2008; 15(10): 2833 - 2841. [Abstract] [Full Text] [PDF]

				A. O. Rehman and C.-Y. Wang SDF-1{alpha} Promotes Invasion of Head and Neck Squamous Cell Carcinoma by Activating NF-{kappa}B J. Biol. Chem., July 18, 2008; 283(29): 19888 - 19894. [Abstract] [Full Text] [PDF]

				F. Diomedi-Camassei, H. P. McDowell, M. A. De Ioris, S. Uccini, P. Altavista, G. Raschella, R. Vitali, O. Mannarino, L. De Sio, D. A. Cozzi, et al. Clinical Significance of CXC Chemokine Receptor-4 and c-Met in Childhood Rhabdomyosarcoma Clin. Cancer Res., July 1, 2008; 14(13): 4119 - 4127. [Abstract] [Full Text] [PDF]

				P. T. Winnard Jr., A. P. Pathak, S. Dhara, S. Y. Cho, V. Raman, and M. G. Pomper Molecular Imaging of Metastatic Potential J. Nucl. Med., June 1, 2008; 49(Suppl_2): 96S - 112S. [Abstract] [Full Text] [PDF]

				Z. Wang, L. Zhang, A. Qiao, K. Watson, J. Zhang, and G.-H. Fan Activation of CXCR4 Triggers Ubiquitination and Down-regulation of Major Histocompatibility Complex Class I (MHC-I) on Epithelioid Carcinoma HeLa Cells J. Biol. Chem., February 15, 2008; 283(7): 3951 - 3959. [Abstract] [Full Text] [PDF]

				H. Li, H. Alizadeh, and J. Y. Niederkorn Differential Expression of Chemokine Receptors on Uveal Melanoma Cells and Their Metastases Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 636 - 643. [Abstract] [Full Text] [PDF]

				A. Richmond CCR9 Homes Metastatic Melanoma Cells to the Small Bowel Clin. Cancer Res., February 1, 2008; 14(3): 621 - 623. [Full Text] [PDF]

				J. M. Reese, D. Phillips, J. A. Brown, and J. C. Papadimitriou Metastatic Carcinoma Within a Foreign-Body Reaction to Vegetable Matter: A Pseudo-Pseudomalignancy International Journal of Surgical Pathology, January 1, 2008; 16(1): 59 - 61. [PDF]

				C.-H. Tang, T.-W. Tan, W.-M. Fu, and R.-S. Yang Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis Carcinogenesis, January 1, 2008; 29(1): 35 - 43. [Abstract] [Full Text] [PDF]

				Z. Miao, K. E. Luker, B. C. Summers, R. Berahovich, M. S. Bhojani, A. Rehemtulla, C. G. Kleer, J. J. Essner, A. Nasevicius, G. D. Luker, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature PNAS, October 2, 2007; 104(40): 15735 - 15740. [Abstract] [Full Text] [PDF]

				Y.-C. Chiu, R.-S. Yang, K.-H. Hsieh, Y.-C. Fong, T.-D. Way, T.-S. Lee, H.-C. Wu, W.-M. Fu, and C.-H. Tang Stromal Cell-Derived Factor-1 Induces Matrix Metalloprotease-13 Expression in Human Chondrocytes Mol. Pharmacol., September 1, 2007; 72(3): 695 - 703. [Abstract] [Full Text] [PDF]

				J. M. Cerutti, G. Oler, P. Michaluart Jr., R. Delcelo, R. M. Beaty, J. Shoemaker, and G. J. Riggins Molecular Profiling of Matched Samples Identifies Biomarkers of Papillary Thyroid Carcinoma Lymph Node Metastasis Cancer Res., August 15, 2007; 67(16): 7885 - 7892. [Abstract] [Full Text] [PDF]

				E. L. Hsu, D. Yoon, H. H. Choi, F. Wang, R. T. Taylor, N. Chen, R. Zhang, and O. Hankinson A Proposed Mechanism for the Protective Effect of Dioxin against Breast Cancer Toxicol. Sci., August 1, 2007; 98(2): 436 - 444. [Abstract] [Full Text] [PDF]

				J. M. Petty, V. Sueblinvong, C. C. Lenox, C. C. Jones, G. P. Cosgrove, C. D. Cool, P. R. Rai, K. K. Brown, D. J. Weiss, M. E. Poynter, et al. Pulmonary Stromal-Derived Factor-1 Expression and Effect on Neutrophil Recruitment during Acute Lung Injury J. Immunol., June 15, 2007; 178(12): 8148 - 8157. [Abstract] [Full Text] [PDF]

				M. Wysoczynski, K. Miekus, K. Jankowski, J. Wanzeck, S. Bertolone, A. Janowska-Wieczorek, J. Ratajczak, and M. Z. Ratajczak Leukemia Inhibitory Factor: A Newly Identified Metastatic Factor in Rhabdomyosarcomas Cancer Res., March 1, 2007; 67(5): 2131 - 2140. [Abstract] [Full Text] [PDF]

				I. Kryczek, S. Wei, E. Keller, R. Liu, and W. Zou Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis Am J Physiol Cell Physiol, March 1, 2007; 292(3): C987 - C995. [Abstract] [Full Text] [PDF]

				O. Wald, U. Izhar, G. Amir, S. Avniel, Y. Bar-Shavit, H. Wald, I. D. Weiss, E. Galun, and A. Peled CD4+CXCR4highCD69+ T Cells Accumulate in Lung Adenocarcinoma J. Immunol., November 15, 2006; 177(10): 6983 - 6990. [Abstract] [Full Text] [PDF]

				J. D. Holland, M. Kochetkova, C. Akekawatchai, M. Dottore, A. Lopez, and S. R. McColl Differential functional activation of chemokine receptor CXCR4 is mediated by g proteins in breast cancer cells. Cancer Res., April 15, 2006; 66(8): 4117 - 4124. [Abstract] [Full Text] [PDF]

				B. N. Gomperts and R. M. Strieter CXC Chemokines in Angiogenesis and Metastases Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 11 - 18. [Full Text] [PDF]

				C. Akekawatchai, J. D. Holland, M. Kochetkova, J. C. Wallace, and S. R. McColl Transactivation of CXCR4 by the Insulin-like Growth Factor-1 Receptor (IGF-1R) in Human MDA-MB-231 Breast Cancer Epithelial Cells J. Biol. Chem., December 2, 2005; 280(48): 39701 - 39708. [Abstract] [Full Text] [PDF]

				E. L. Snyder, C. C. Saenz, C. Denicourt, B. R. Meade, X.-S. Cui, I. M. Kaplan, and S. F. Dowdy Enhanced Targeting and Killing of Tumor Cells Expressing the CXC Chemokine Receptor 4 by Transducible Anticancer Peptides Cancer Res., December 1, 2005; 65(23): 10646 - 10650. [Abstract] [Full Text] [PDF]

				J. Mestas, M. D. Burdick, K. Reckamp, A. Pantuck, R. A. Figlin, and R. M. Strieter The Role of CXCR2/CXCR2 Ligand Biological Axis in Renal Cell Carcinoma J. Immunol., October 15, 2005; 175(8): 5351 - 5357. [Abstract] [Full Text] [PDF]

				D. Zagzag, B. Krishnamachary, H. Yee, H. Okuyama, L. Chiriboga, M. A. Ali, J. Melamed, and G. L. Semenza Stromal Cell-Derived Factor-1{alpha} and CXCR4 Expression in Hemangioblastoma and Clear Cell-Renal Cell Carcinoma: von Hippel-Lindau Loss-of-Function Induces Expression of a Ligand and Its Receptor Cancer Res., July 15, 2005; 65(14): 6178 - 6188. [Abstract] [Full Text] [PDF]

				J. Hu, X. Deng, X. Bian, G. Li, Y. Tong, Y. Li, Q. Wang, R. Xin, X. He, G. Zhou, et al. The Expression of Functional Chemokine Receptor CXCR4 Is Associated with the Metastatic Potential of Human Nasopharyngeal Carcinoma Clin. Cancer Res., July 1, 2005; 11(13): 4658 - 4665. [Abstract] [Full Text] [PDF]

				R. J. Phillips, J. Mestas, M. Gharaee-Kermani, M. D. Burdick, A. Sica, J. A. Belperio, M. P. Keane, and R. M. Strieter Epidermal Growth Factor and Hypoxia-induced Expression of CXC Chemokine Receptor 4 on Non-small Cell Lung Cancer Cells Is Regulated by the Phosphatidylinositol 3-Kinase/PTEN/AKT/Mammalian Target of Rapamycin Signaling Pathway and Activation of Hypoxia Inducible Factor-1{alpha} J. Biol. Chem., June 10, 2005; 280(23): 22473 - 22481. [Abstract] [Full Text] [PDF]

				A. Katayama, T. Ogino, N. Bandoh, S. Nonaka, and Y. Harabuchi Expression of CXCR4 and Its Down-Regulation by IFN-{gamma} in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., April 15, 2005; 11(8): 2937 - 2946. [Abstract] [Full Text] [PDF]

				C. Laverdiere, B. H. Hoang, R. Yang, R. Sowers, J. Qin, P. A. Meyers, A. G. Huvos, J. H. Healey, and R. Gorlick Messenger RNA Expression Levels of CXCR4 Correlate with Metastatic Behavior and Outcome in Patients with Osteosarcoma Clin. Cancer Res., April 1, 2005; 11(7): 2561 - 2567. [Abstract] [Full Text] [PDF]

				C. C. Schimanski, S. Schwald, N. Simiantonaki, C. Jayasinghe, U. Gonner, V. Wilsberg, T. Junginger, M. R. Berger, P. R. Galle, and M. Moehler Effect of Chemokine Receptors CXCR4 and CCR7 on the Metastatic Behavior of Human Colorectal Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1743 - 1750. [Abstract] [Full Text] [PDF]

				J. M. Smith, P. A. Johanesen, M. K. Wendt, D. G. Binion, and M. B. Dwinell CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity Am J Physiol Gastrointest Liver Physiol, February 1, 2005; 288(2): G316 - G326. [Abstract] [Full Text] [PDF]

				E. Piovan, V. Tosello, S. Indraccolo, A. Cabrelle, I. Baesso, L. Trentin, R. Zamarchi, H. Tamamura, N. Fujii, G. Semenzato, et al. Chemokine receptor expression in EBV-associated lymphoproliferation in hu/SCID mice: implications for CXCL12/CXCR4 axis in lymphoma generation Blood, February 1, 2005; 105(3): 931 - 939. [Abstract] [Full Text] [PDF]

				C. Murdoch, A. Giannoudis, and C. E. Lewis Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Blood, October 15, 2004; 104(8): 2224 - 2234. [Abstract] [Full Text] [PDF]

				G. G. Vaday, S.-B. Hua, D. M. Peehl, M. H. Pauling, Y.-H. Lin, L. Zhu, D. M. Lawrence, H. D. Foda, and S. Zucker CXCR4 and CXCL12 (SDF-1) in Prostate Cancer: Inhibitory Effects of Human Single Chain Fv Antibodies Clin. Cancer Res., August 15, 2004; 10(16): 5630 - 5639. [Abstract] [Full Text] [PDF]

				D. Arenberg In Search of the Holy Grail: Lung Cancer Biomarkers Chest, August 1, 2004; 126(2): 325 - 326. [Full Text] [PDF]

				K.-i. Oonakahara, W. Matsuyama, I. Higashimoto, M. Kawabata, K. Arimura, and M. Osame Stromal-Derived Factor-1{alpha}/CXCL12-CXCR 4 Axis Is Involved in the Dissemination of NSCLC Cells into Pleural Space Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 671 - 677. [Abstract] [Full Text] [PDF]

				J.-P. Spano, F. Andre, L. Morat, L. Sabatier, B. Besse, C. Combadiere, P. Deterre, A. Martin, J. Azorin, D. Valeyre, et al. Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome Ann. Onc., April 1, 2004; 15(4): 613 - 617. [Abstract] [Full Text] [PDF]

				M. P. Keane, J. A. Belperio, Y. Y. Xue, M. D. Burdick, and R. M. Strieter Depletion of CXCR2 Inhibits Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer J. Immunol., March 1, 2004; 172(5): 2853 - 2860. [Abstract] [Full Text] [PDF]

				M. J. Tobin Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003 Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313. [Full Text] [PDF]