Expression and function of CXCR4 in human salivary gland cancers
- 616 Downloads
Salivary gland cancers (SGCs) frequently metastasize to cervical lymph nodes and distant organs. Currently, the mechanisms responsible for the metastatic behavior of SGC cells are not fully understood. We previously demonstrated that the stromal cell-derived factor-1 (SDF-1; also known as CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral squamous cell carcinoma. In the present study, we investigated the role of CXCR4 in the metastatic behavior of SGCs. We examined the expression of CXCR4 mRNA and protein in human SGC cell lines by quantitative RT-PCR and western blotting, respectively. The expression of CXCR4 mRNA and protein were frequently upregulated in 5 out of 6 SGC cell lines. Functional CXCR4 expression was demonstrated by the ability of these SGC cell lines to migrate toward an SDF-1 gradient. SDF-1 rapidly activated extracellular signal-regulated kinase (ERK)1/2 in SGC cell lines. Immunohistochemical analysis revealed that CXCR4 protein expression was detected in either the nucleus or cytoplasm of cancer cells in 16 out of 20 tissues of adenoid cystic carcinoma (ACC) and in 4 out of 6 tissues of mucoepidermoid carcinoma, which are representative of SGC. Furthermore, ACC cell lines exhibited dramatic metastasis to the lung following intravenous inoculation, whereas AMD3100, a CXCR4 antagonist, significantly inhibited lung metastasis of the cells, ameliorated body weight loss and improved the survival rate of tumor-bearing nude mice. These results indicate that CXCR4 expression contributes to the metastatic potential of SGCs.
KeywordsSalivary gland cancers CXCR4 Metastases Adenoid cystic carcinoma Mucoepidermoid carcinoma
Salivary gland cancers
Adenoid cystic carcinoma
We thank Dr. Naozumi Ishimaru (Department of Oral Molecular Pathology, Tokushima University School of Dentistry) for valuable advice on histopathology. We also thank Drs. Tomitaro Onoue and Begum Nasima-Mila for technical assistance. This study was supported in part by a Grant-in-Aid for Scientific Research (C) (23592964).
- 3.Barnes L, Eveson JW, Reichart P, Sidransky D (2005) World Health Organization classification of tumors: pathology and genetics of the head and neck tumours. IARC Press, LyonGoogle Scholar
- 29.Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203(9):2201–2213PubMedCrossRefGoogle Scholar
- 36.Tilton B, Ho L, Oberlin E, Loetscher P, Baleux F, Clark-Lewis I, Thelen M (2000) Signal transduction by CXC chemokine receptor 4. Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes. J Exp Med 192(3):313–324PubMedCrossRefGoogle Scholar
- 38.Ganju RK, Brubaker SA, Meyer J, Dutt P, Yang Y, Qin S, Newman W, Groopman JE (1998) The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J Biol Chem 273(36):23169–23175PubMedCrossRefGoogle Scholar
- 42.Muller A, Sonkoly E, Eulert C, Gerber PA, Kubitza R, Schirlau K, Franken-Kunkel P, Poremba C, Snyderman C, Klotz LO, Ruzicka T, Bier H, Zlotnik A, Whiteside TL, Homey B, Hoffmann TK (2006) Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy. Int J Cancer 118(9):2147–2157PubMedCrossRefGoogle Scholar