Abstract
Background
The stromal cell-derived factor-1/CXC chemokine receptor-4 (SDF-1/CXCR4) signal has been shown to be important in various immunological reactions. Recent studies have suggested that CXCR4 is expressed in certain cancer cells and that they use this chemokine receptor efficiently for metastasis formation.
Method
The expression of CXCR4 was evaluated by immunohistochemical study in 79 surgically resected invasive ductal carcinomas, and the relation between the staining pattern and clinicopathological features was examined.
Results
CXCR4 was diffusely and homogeneously expressed in 59 cancers, which were further divided into 28 high-expression and 31 low-expression cancers by their staining intensity. The other 20 cancers showed heterogeneous immunoreactivity in tumor tissue, which was defined as focal type. In comparison with the diffuse type, focal type tumors showed significantly more extensive lymph node metastasis, because the number and extent of metastatic nodes were larger in the focal than the diffuse type. In the diffuse type, the rate of node-positive cases did not show a difference in staining intensity. However, high-CXCR4 tumors showed more extensive nodal metastasis in comparison with low-expression tumors. In contrast, the expression pattern of CXCR4 did not have a significant correlation with hematogeneous metastasis. The overall survival of these patients tended to be better in the diffuse type than in the focal type, although the difference was not statistically significant.
Conclusion
The expression pattern of CXCR4 was significantly correlated with the degree of lymph node metastasis in breast cancers. Our data suggest that CXCR4 might be particularly important in facilitating metastasis through the lymphatic system.
Similar content being viewed by others
Abbreviations
- CXCR4:
-
CC chemokine receptor-4
- SDF-1:
-
stromal cell-derived factor-1.
References
Rollins BJ: Chemokines. Blood. 1997, 90: 909-928.
Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA: A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996, 184: 1101-1109.
Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T: Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996, 382: 635-638. 10.1038/382635a0.
Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA: The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996, 382: 829-833. 10.1038/382829a0.
Hardy C: Homing of hematopoietic stem cells to the marrow. Am J Med Sci. 1995, 309: 260-266.
Kim CH, Broxmeyer HE: SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation. J Leuk Biol. 1999, 66: 455-461.
Aiuti A, Tavian M, Cipponi A, Ficara F, Zappone E, Hoxie J, Peault B, Bordignon C: Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lympho-hematopoietic progenitors. Eur J Immunol. 1999, 29: 1823-1831. 10.1002/(SICI)1521-4141(199906)29:06<1823::AID-IMMU1823>3.0.CO;2-B.
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001, 410: 50-56. 10.1038/35065016.
Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP, Ben-Baruch A: A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol. 2001, 167: 4747-4757.
Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK: Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002, 62: 1832-1837.
Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M, Marquez L, Peiper SC, Barr FG, Janowska-Wieczorek A, Ratajczak MZ: CXCR4-SDF-1 signaling is active in rhabdomyosar-coma cells and regulates locomotion, chemotaxis, and adhesion. Blood. 2002, 100: 2597-2606. 10.1182/blood-2002-01-0031.
Liotta LA: An attractive force in metastasis. Nature. 2001, 410: 24-25. 10.1038/35065180.
Murphy PM: Chemokines and the molecular basis of cancer metastasis. N Engl J Med. 2001, 345: 833-835. 10.1056/NEJM200109133451113.
Lavi E, Strizki JM, Ulrich AM, Zhang W, Fu L, Wang Q, O'Connor M, Hoxie JA, Gonzalez-Scarano F: CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. Am J Pathol. 1997, 151: 1035-1042.
Van Der Meer P, Goldberg SH, Fung KM, Sharer LR, Gonzalez-Scarano F, Lavi E: Expression pattern of CXCR3, CXCR4, and CCR3 chemokine receptors in the developing human brain. J Neuropathol Exp Neurol. 2001, 60: 25-32.
Jordan NJ, Kolios G, Abbot SE, Sinai MA, Thompson DA, Petraki K, Westwick J: Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. J Clin Invest. 1999, 104: 1061-1069.
Zhou Y, Larsen PH, Hao C, Yong VW: CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem. 2002, 277: 49481-49487. 10.1074/jbc.M206222200.
Hwang JH, Hwang JH, Chung HK, Kim DW, Hwang ES, Suh JM, Kim H, You KH, Kwon OY, Ro HK, Jo DY, Shong M: CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. J Clin Endocrinol Metab. 2003, 88: 408-416. 10.1210/jc.2002-021381.
Schrader AJ, Lechner O, Templin M, Dittmar KE, Machtens S, Mengel M, Probst-Kepper M, Franzke A, Wollensak T, Gatzlaff P, Atzpodien J, Buer J, Lauber J: CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer. 2002, 86: 1250-1256. 10.1038/sj.bjc.6600221.
Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, Bridger G, Balkwill FR: Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 2002, 62: 5930-5938.
Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sanchez-Mateos P, Teixido J: Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. J Biol Chem. 2001, 276: 45098-45105. 10.1074/jbc.M106912200.
Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M: Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res. 2000, 6: 3530-3535.
Corcione A, Ottonello L, Tortolina G, Facchetti P, Airoldi I, Guglielmino R, Dadati P, Truini M, Sozzani S, Dallegri F, Pistoia V: Stromal cell-derived factor-1 as a chemoattractant for follicular center lymphoma B cells. J Natl Cancer Inst. 2000, 92: 628-635. 10.1093/jnci/92.8.628.
Arai J, Yasukawa M, Yakushijin Y, Miyazaki T, Fujita S: Stromal cells in lymph nodes attract B-lymphoma cells via production of stromal cell-derived factor-1. Eur J Haematol. 2000, 64: 323-332. 10.1034/j.1600-0609.2000.90147.x.
Chambers AF, Groom AC, MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002, 2: 563-572. 10.1038/nrc865.
Helbig G, Christopherson KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H: NF-κB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem.
Perrone F, Carlomagno C, Lauria R, De Laurentiis M, Morabito A, Panico L, Pettinato G, Petrella G, Gallo C, Bianco AR, De Placido S: Selecting high-risk early breast cancer patients: what to add to the number of metastatic nodes?. Eur J Cancer. 1996, 32A: 41-46. 10.1016/0959-8049(95)00442-4.
Zurrida S, Morabito A, Galimberti V, Luini A, Greco M, Bartoli C, Raselli R, Rossi N, Vessecchia G, Cascinelli N, Veronesi U: Importance of the level of axillary involvement in relation to traditional variables in the prognosis of breast cancer. Int J Oncol. 1999, 15: 475-480.
Karpeh MS, Leon L, Klimstra D, Brennan MF: Lymph node staging in gastric cancer: is location more important than number? An analysis of 1,038 patients. Ann Surg. 2000, 232: 362-371. 10.1097/00000658-200009000-00008.
Kawahara K, Maekawa T, Okabayashi K, Shiraishi T, Yoshinaga Y, Yoneda S, Hideshima T, Shirakusa T: The number of lymph node metastases influences survival in esophageal cancer. J Surg Oncol. 1998, 67: 160-163. 10.1002/(SICI)1096-9098(199803)67:3<160::AID-JSO3>3.0.CO;2-7.
Roder JD, Schneider PM, Stein HJ, Siewert JR: Number of lymph node metastases is significantly associated with survival in patients with radically resected carcinoma of the ampulla of Vater. Br J Surg. 1995, 82: 1693-1696.
Inoue T, Morita K: The prognostic significance of number of positive nodes in cervical carcinoma stages IB, IIA, and IIB. Cancer. 1990, 65: 1923-1927.
Acknowledgement
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and by a Grant from the Ministry of Health and Welfare of Japan.
Author information
Authors and Affiliations
Corresponding author
Additional information
Competing interests
None declared.
Rights and permissions
About this article
Cite this article
Kato, M., Kitayama, J., Kazama, S. et al. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res 5, R144 (2003). https://doi.org/10.1186/bcr627
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1186/bcr627