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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Cytoplasmic CXCR4 expression in breast cancer: induction by nitric oxide and correlation with lymph node metastasis and poor prognosis

Authors: Hironao Yasuoka, Masahiko Tsujimoto, Katsuhide Yoshidome, Masaaki Nakahara, Rieko Kodama, Tokio Sanke, Yasushi Nakamura

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

Lymph nodes constitute the first site of metastasis for most malignancies, and the extent of lymph node involvement is a major criterion for evaluating patient prognosis. The CXC chemokine receptor 4 (CXCR4) has been shown to play an important role in lymph node metastasis. Nitric oxide (NO) may also contribute to induction of metastatic ability in human cancers.

Methods

CXCR4 expression was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels (a biomarker for peroxynitrate formation from NO in vivo) and lymph node status, CXCR4 immunoreactivity, and other established clinico-pathological parameters, as well as prognosis, was analyzed. Nitrite/nitrate levels and CXCR4 expressions were assessed in MDA-MB-231 and SK-BR-3 breast cancer cell lines after induction and/or inhibition of NO synthesis.

Results

CXCR4 staining was predominantly cytoplasmic; this was observed in 50%(56/113) of the tumors. Cytoplasmic CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis. Kaplan-Meier survival curves showed that cytoplasmic CXCR4 expression was associated with reduced disease-free and overall survival. In multivariate analysis, cytoplasmic CXCR4 expression emerged as a significant independent predictor for overall and disease-free survival. Cytoplasmic expression of functional CXCR4 in MDA-MB-231 and SK-BR-3 cells was increased by treatment with the NO donor DETA NONOate. This increase was abolished by L-NAME, an inhibitor of NOS.

Conclusion

Our data showed a role for NO in stimulating cytoplasmic CXCR4 expression in vitro. Formation of the biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in vivo. In addition, cytoplasmic CXCR4 expression may serve as a significant prognostic factor for long-term survival in breast cancer.
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Literature
1.
Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG: The role of nitric oxide in cancer. Cell Res. 2002, 12 (5–6): 311-320. 10.1038/sj.cr.7290133.CrossRefPubMed
2.
Ambs S, Merriam WG, Ogunfusika MO, Bennett WP, Ishibe N, Hussain SP, Tzeng EE, Geller DA, Billiar TR, Harris CC: p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med. 1998, 4 (12): 1371-1376. 10.1038/3957.CrossRefPubMed
3.
Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, Nakamura M, Kakudo K: Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res. 2006, 12 (4): 1201-1207. 10.1158/1078-0432.CCR-05-1269.CrossRefPubMed
4.
Beckman JS: Oxidative damage and tyrosine nitration from peroxynitrite. Chem Res Toxicol. 1996, 9 (5): 836-844. 10.1021/tx9501445.CrossRefPubMed
5.
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001, 410 (6824): 50-56. 10.1038/35065016.CrossRefPubMed
6.
Cabioglu N, Yazici MS, Arun B, Broglio KR, Hortobagyi GN, Price JE, Sahin A: CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin Cancer Res. 2005, 11 (16): 5686-5693. 10.1158/1078-0432.CCR-05-0014.CrossRefPubMed
7.
Salvucci O, Bouchard A, Baccarelli A, Deschenes J, Sauter G, Simon R, Bianchi R, Basik M: The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study. Breast Cancer Res Treat. 2006, 97 (3): 275-283. 10.1007/s10549-005-9121-8.CrossRefPubMed
8.
Nakamura Y, Yasuoka H, Zuo H, Takamura Y, Miyauchi A, Nakamura M, Kakudo K: Nitric oxide in papillary thyroid carcinoma: induction of vascular endothelial growth factor d and correlation with lymph node metastasis. J Clin Endocrinol Metab. 2006, 91 (4): 1582-1585. 10.1210/jc.2005-1790.CrossRefPubMed
9.
Edwards P, Cendan JC, Topping DB, Moldawer LL, MacKay S, Copeland E, Lind DS: Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J Surg Res. 1996, 63 (1): 49-52. 10.1006/jsre.1996.0221.CrossRefPubMed
10.
Helbig G, Christopherson KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H: NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003, 278 (24): 21631-21638. 10.1074/jbc.M300609200.CrossRefPubMed
11.
Cherla RP, Ganju RK: Stromal cell-derived factor 1 alpha-induced chemotaxis in T cells is mediated by nitric oxide signaling pathways. J Immunol. 2001, 166 (5): 3067-3074.CrossRefPubMed
12.
Hao L, Zhang C, Qiu Y, Wang L, Luo Y, Jin M, Zhang Y, Guo TB, Matsushima K: Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett. 2007, 253 (1): 34-42. 10.1016/j.canlet.2007.01.005.CrossRefPubMed
13.
Bachelder RE, Wendt MA, Mercurio AM: Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res. 2002, 62 (24): 7203-7206.PubMed
14.
Liang Z, Brooks J, Willard M, Liang K, Yoon Y, Kang S, Shim H: CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun. 2007, 359 (3): 716-722. 10.1016/j.bbrc.2007.05.182.CrossRefPubMedPubMedCentral
15.
Tavassoli FA, Devilee P: World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. 2003, IARC Press: Lyon
16.
Bloom HJ, Richardson WW: Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957, 11 (3): 359-377.CrossRefPubMedPubMedCentral
17.
Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med. 1993, 329 (27): 2002-2012. 10.1056/NEJM199312303292706.CrossRefPubMed
18.
19.
Franchi A, Massi D, Santucci M, Masini E, Degl'innocenti DR, Magnelli L, Fanti E, Naldini A, Ardinghi C, Carraro F, et al: Inducible nitric oxide synthase activity correlates with lymphangiogenesis and vascular endothelial growth factor-C expression in head and neck squamous cell carcinoma. J Pathol. 2006, 208 (3): 439-445. 10.1002/path.1892.CrossRefPubMed
20.
Balkwill F: Cancer and the chemokine network. Nat Rev Cancer. 2004, 4 (7): 540-550. 10.1038/nrc1388.CrossRefPubMed
21.
Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN, Yu D, et al: Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell. 2004, 6 (5): 459-469. 10.1016/j.ccr.2004.09.027.CrossRefPubMed
22.
Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, et al: Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003, 198 (9): 1391-1402. 10.1084/jem.20030267.CrossRefPubMedPubMedCentral
23.
Baribaud F, Edwards TG, Sharron M, Brelot A, Heveker N, Price K, Mortari F, Alizon M, Tsang M, Doms RW: Antigenically distinct conformations of CXCR4. J Virol. 2001, 75 (19): 8957-8967. 10.1128/JVI.75.19.8957-8967.2001.CrossRefPubMedPubMedCentral
24.
Chang Y, Ceacareanu B, Dixit M, Sreejayan N, Hassid A: Nitric oxide-induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 and GTP-binding protein Rho. Circ Res. 2002, 91 (5): 390-397. 10.1161/01.RES.0000033524.92083.64.CrossRefPubMed
25.
Tan CT, Chu CY, Lu YC, Chang CC, Lin BR, Wu HH, Liu HL, Cha ST, Prakash E, Ko JY, et al: CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway. Carcinogenesis. 2008, 29 (8): 1519-1527. 10.1093/carcin/bgn108.CrossRefPubMed
26.
Na IK, Scheibenbogen C, Adam C, Stroux A, Ghadjar P, Thiel E, Keilholz U, Coupland SE: Nuclear expression of CXCR4 in tumor cells of non-small cell lung cancer is correlated with lymph node metastasis. Hum Pathol. 2008
27.
Yoshitake N, Fukui H, Yamagishi H, Sekikawa A, Fujii S, Tomita S, Ichikawa K, Imura J, Hiraishi H, Fujimori T: Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer. 2008, 98 (10): 1682-1689. 10.1038/sj.bjc.6604363.CrossRefPubMedPubMedCentral
28.
van Buul JD, Voermans C, van Gelderen J, Anthony EC, Schoot van der CE, Hordijk PL: Leukocyte-endothelium interaction promotes SDF-1-dependent polarization of CXCR4. J Biol Chem. 2003, 278 (32): 30302-30310. 10.1074/jbc.M304764200.CrossRefPubMed
29.
Gortz A, Nibbs RJ, McLean P, Jarmin D, Lambie W, Baird JW, Graham GJ: The chemokine ESkine/CCL27 displays novel modes of intracrine and paracrine function. J Immunol. 2002, 169 (3): 1387-1394.CrossRefPubMed
30.
Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F: The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005, 280 (42): 35760-35766. 10.1074/jbc.M508234200.CrossRefPubMed
31.
Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, et al: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006, 203 (9): 2201-2213. 10.1084/jem.20052144.CrossRefPubMedPubMedCentral
32.
Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, et al: CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA. 2007, 104 (40): 15735-15740. 10.1073/pnas.0610444104.CrossRefPubMedPubMedCentral
Metadata
Title
Cytoplasmic CXCR4 expression in breast cancer: induction by nitric oxide and correlation with lymph node metastasis and poor prognosis
Authors
Hironao Yasuoka
Masahiko Tsujimoto
Katsuhide Yoshidome
Masaaki Nakahara
Rieko Kodama
Tokio Sanke
Yasushi Nakamura
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-340

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