Expression of the CXCR4 and CCR7 chemokine receptors in human endometrial cancer

Purpose: The chemokine receptors CXCR4 and CCR7 have been suggested to play an important role in cancer progression but their expression in human endometrial cancer has not been fully characterized. The aim of this study was to investigate CXCR4 and CCR7 expression in endometrial cancers.

Methods: We immunohistochemically investigated the expression of CXCR4 and CCR7 protein in 166 endometrial cancers and analyzed the correlation with various observed clinicopathological features, including patient outcome. Fresh tumor specimens were obtained from 55 of the 166 endometrial cancer patients, and the expression levels of the CXCR4 and CCR7 genes were also examined in this subgroup.

Results: Our results indicate that CXCR4 and CCR7 transcripts levels are significantly higher in tumors that express the corresponding protein products. CXCR4 and CCR7 protein expression levels were found to be significantly lower in patients with endometrial tumors of a high grade. Consistent with this, the overall survival rates were significantly better in patients exhibiting higher levels of CXCR4 and CCR7 expression.

Conclusion: We thus hypothesize that CXCR4 and CCR7 protein levels are suppressed in high-grade endometrial tumors, but that the expression of these receptors per se may not be a crucial role in tumor progression or metastasis in these cancers.

CXCR4; CCR7; Endometrial cancer

[1] Baggiolini M., Dewald B., Moser B.: "Human chemokmes: an update". Annu. Rev. lmmunol., 1997, 15,675.

[2] Rollins BJ.: "Chemokines". Blood, 1997, 90, 909.

[3] Kelner G.S., Kennedy J., Bacon K.B. et al.: "Lymphoactrn: a cytokine that represents a new class of chemokines". Science, 1994, 266, 1395.

[4] Arya M.,P atel H.R.,W illiamson M.: "Chemokines: key players in cancer". Cun: Med. Res. Opin., 2003, 19, 557.

[5] Balkwill F.: "The significance of cancer cell expression of the chemokine receptor CXCR4". Semin. cancer. Biol., 2004, 14, 171.

[6] Murdoch C.: "CXCR4: chemokine receptors extraordinaire". lmmunol. Rev., 2000, 177, 175.

[7] Murphy P.M.: "Chemokines and the molecular basis of cancer metastasis". N. Engl. J. Med., 2001, 345, 833.

[8] Dieu M.C.,V anbervliet B.,V icari A. et al.: "Selective recruitment of immature and mature dendritic cell by distinct chemokine expression in different anatomic sites". J. Exp. Med., 1998, 188, 373.

[9] Hirano M., Onai N., H订oishi K. et al.: "CC chemo伈ne receptor-7 on dendritic cells in induced after interaction with apoptotic tumor cells: critical role in migration from the tumor site to draining lymph nodes". Cancer Res., 2000, 60, 2209.

[10] Kodama J., Hasengaowa, Kusumoto T. et al.: "Association of CXCR4 and CCR7 chemikne receptor expression and lymph node metastasis in human cervical cancer". Ann. Oncol., 2007, 18, 70.

[11] Scotton CJ., Wilson J.L., Milliken D., Stamp G., Balkwill E.R "Epithelial cancer cell migration: a role for chemokine receptors" Cancer Res., 2001, 61, 4961.

[12] Koshiba T., Hosotani R., Miyamoto Y. et al.: "Expression of stromal cell-derived factor I and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression". Clin. Cancer Res., 2000, 6, 3530.

[13] Yanagihara S., Komura E., Nagafune J., Watari H., Yamaguchi Y. "EBI1/CCR7 is a new member of dendritic cell chemokine receptor that is up-regulation upon maturation". J. Immunol., 1998, 161, 3096.

[14] Mizokami Y., Kajiyama H., Shibata K. et al.: "Stromal cellderived factor-1ð nduced cell proliferation and its possible regulation by CD26/Dipeptidyl peptidase IV in endometrial adenocarcinoma". Int. J. Cancer, 2004, l 10, 652.

[15] Kwak M.K., Hur K., Park D.J. et al.: "Expression of chemokme receptors in human gastric cancer". Tumor Biol., 2005, 26, 65.

[16] Mori T., Kim J., Yamano T., Takeuchi H. et al.: "Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells". Cancer Res., 2005, 65, 1800.

[17] Sato N., Matubayashi H., Fukushima N., Goggins M.: "The chemokine receptor CXCR4 is regulated by DNA methylation in pancreatic cancer". Cancer Biol. Ther., 2005, 74, 70.

[18] Muller A., Homey B., Soto H. et al.: "Involvement of chemokine receptors in breast cancer metastasis". Nature, 2001, 410, 50.

[19] Spano J.P., Andre F., Morat L. et al.: "Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome". Ann. Oneal., 2004, 15, 613.

[20] Koshiba T., Hosotani R., Miyamoto Y. et al.: "Expression of stromal cell-derived factor I and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression". Clin Cancer Res., 6, 2000, 3530.

[21] Taichman R.S., Cooper C., Keller E.T. et al.: "Use of the stromal cell-derived factor- l/CXCR4 pathway in prostate cancer metastasis to bone". Cancer Res., 2002, 62, 1832.

[22] Hwang J.H., Hwang J.H., Chung H.K. et al.: "CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells". J. Clin. Endocrinol. Metah., 2003, 88, 408.

[23] Scotton C.J., Wilson J.L., Scott K. et al.: "Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer". Cancer Res., 2002, 62, 5930.

[24] Hu J., Deng X., Bian X. et al.: "The expression of functional chemokine receptor CXCR4 is associated with the metastatic potential of human nasopharyngeal carcinoma". Clin. Cancer Res., 2005, 11, 4658.

[25] Scala S., Ottaiano A., Ascierto P.A. et al.: "Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma" Clin. Cancer Res., 2005, I I, 1835.

[26] Laverdiere C.. Hoang B.H., Yang R. et al.: "Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma". Clin. Cancer Res., 2005, 11, 2561.

[27] Lambeir A., Proost P., Durinx C. et al.: "Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family". J. Biol. Chem., 2001, 276, 29839.

[28] Delgado M., Clark-Lewis I., Loetscher P. et al.: "Rapid inactivation of stromal cell-derived factor- I by cathepsin G associated with lymphocytes". Eur. J. Immunol., 2001, 31, 699.

[29] McQuibban G., Butler G., Gong J. et al.: "Matrix metalloproteinase activity inactivates the CXC chemokine stromal cellderived factor-1". J. Biol. Chem., 2001, 276, 43503.

[30] Valenzuela-Fernandez A., Planchenault T., Beleux F. et al.: "Leukocyte elastase negatively regulates stromal cell-derived factor-I (SDF- l)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4". J. Biol. Chem., 2002, 277, 15677.

[31] Cabioglu N., Yazici M.S., Arun B. et al.: "CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in TI breast cancer". Clin. Cancer Res., 2005, I I, 5686.

[32] Takanami I.: "Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis". Int. J. Cancer, 2003, 105, 186.

[33] Mashino K., Sadanaga N., Yamaguchi H. et al.: "Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric cancer". Cancer Res., 2002, 62, 2937.

[34] Giinther K., Leier J., Henning G. et al.: "Predictor of lymph node metastasis in colorectal carcinoma by expression of chemokine receptor CCRT'. Int. J. Cancer, 2005, I 16, 726.

[35] Ding Y., Shimada Y., Maeda M. et al.: "Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma". Clin. Cancer Res., 2003, 9, 3406.

[36] Schmanski C.C., Schwald S., Simiantonaki N. et al.: "Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer". Clin. Cancer Res., 2005, 11, 1743.

[37] Hu J., Deng X., Bian X. et al.: "The expression of functional chemokine receptor CXCR4 is associated with the metastatic potential of humen nasopharyngeal carcinoma". Clin. Cancer Res., 2005, II, 4658.