Prognostic value of the expression of C-Chemokine Receptor 6 and 7 and their ligands in non-metastatic breast cancer

BMC Cancer

Philippe A Cassier²  Isabelle Treilleux¹  Thomas Bachelot²  Isabelle Ray-Coquard³  Nathalie Bendriss-Vermare²  Christine Ménétrier-Caux²  Olivier Trédan³  Sophie Goddard-Léon¹  Jean-Jacques Pin⁴  Hervé Mignotte⁶  Clarisse Bathélémy-Dubois⁵  Christophe Caux²  Serge Lebecque⁴  Jean-Yves Blay⁴ 

[1] Departments of Pathology, Centre Léon Bérard, Lyon, France

[2] Equipe Cytokine et Cancer, INSERM U590, Centre Léon Bérard, Lyon, France

[3] Departments of Medecine, Centre Léon Bérard, Lyon, France

[4] Université Claude Bernard Lyon 1, Lyon, France

[5] Innate Pharma, Marseille, France

[6] Departments of Surgery, Centre Léon Bérard, Lyon, France

关键词: metastasis;    prognosis;    chemokine receptor;    chemokine;    early breast cancer;   

Others  :  1080922
DOI  :  10.1186/1471-2407-11-213

 received in 2010-10-22, accepted in 2011-05-30,  发布年份 2011

【 摘 要 】

Background

Chemokines and chemokine receptors are major actors of leukocytes trafficking and some have been shown to play an important role in cancer metastasis. Chemokines CCL19, CCL20 and CCL21 and their receptors CCR6 and CCR7, were assessed as potential biomarkers of metastatic dissemination in primary breast cancer.

Methods

Biomarker expression levels were evaluated using immunohistochemistry on paraffin-embedded tissue sections of breast cancer (n = 207).

Results

CCR6 was expressed by tumor cells in 35% of cases. CCR7 was expressed by spindle shaped stromal cells in 43% of cases but not by tumor cells in this series. CCL19 was the only chemokine found expressed in a significant number of breast cancers and was expressed by both tumor cells and dendritic cells (DC). CCR6, CCL19 and CCR7 expression correlated with histologic features of aggressive disease. CCR6 expression was associated with shorter relapse-free survival (RFS) in univariate and but not in multivariate analysis (p = 0.0316 and 0.055 respectively), and was not associated with shorter overall survival (OS). Expression of CCR7 was not significantly associated with shorter RFS or OS. The presence of CCL19-expressing DC was associated with shorter RFS in univariate and multivariate analysis (p = 0.042 and 0.020 respectively) but not with shorter OS.

Conclusion

These results suggest a contribution of CCR6 expression on tumor cells and CCL19-expressing DC in breast cancer dissemination. In our series, unlike what was previously published, CCR7 was exclusively expressed on stromal cells and was not associated with survival.

【 授权许可】

   
2011 Cassier et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Punglia RS, Morrow M, Winer EP, Harris JR: Local therapy and survival in breast cancer. N Engl J Med 2007, 356:2399-2405.
• [2]Redding WH, Coombes RC, Monaghan P, Clink HM, Imrie SF, Dearnaley DP, et al.: Detection of micrometastases in patients with primary breast cancer. Lancet 1983, 2:1271-1274.
• [3]Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 365:1687-1717.
• [4]Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al.: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007, 369:29-36.
• [5]Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al.: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410:50-56.
• [6]Eccles SA, Welch DR: Metastasis: recent discoveries and novel treatment strategies. Lancet 2007, 369:1742-1757.
• [7]Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A, et al.: Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol 2006, 17:945-951.
• [8]Cabioglu N, Yazici MS, Arun B, Broglio KR, Hortobagyi GN, Price JE, et al.: CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin Cancer Res 2005, 11:5686-5693.
• [9]Hartmann TN, Burger JA, Glodek A, Fujii N, Burger M: CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 2005, 24:4462-4471.
• [10]Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M: Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 2004, 6:459-469.
• [11]Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, et al.: Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res 2002, 62:2937-2941.
• [12]Singh S, Sadanandam A, Singh RK: Chemokines in tumor angiogenesis and metastasis. Cancer Metastasis Rev 2007, 26:453-467.
• [13]Zlotnik A, Yoshie O, Nomiyama H: The chemokine and chemokine receptor superfamilies and their molecular evolution. Genome Biol 2006, 7:243. BioMed Central Full Text
• [14]Sanchez-Sanchez N, Riol-Blanco L, de la RG, Puig-Kroger A, Garcia-Bordas J, Martin D, et al.: Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood 2004, 104:619-625.
• [15]Scimone ML, Felbinger TW, Mazo IB, Stein JV, Von Andrian UH, Weninger W: CXCL12 mediates CCR7-independent homing of central memory cells, but not naive T cells, in peripheral lymph nodes. J Exp Med 2004, 19;199:1113-1120.
• [16]Forster R, valos-Misslitz AC, Rot A: CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 2008, 8:362-371.
• [17]Kodama J, Kusumoto T, Seki N, Matsuo T, Ojima Y, et al.: Association of CXCR4 and CCR7 chemokine receptor expression and lymph node metastasis in human cervical cancer. Ann Oncol 2007, 18:70-76.
• [18]Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gonner U, Wilsberg V, et al.: Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res 2005, 11:1743-1750.
• [19]Takanami I: Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer 2003, 105:186-189.
• [20]Ghadjar P, Coupland SE, Na IK, Noutsias M, Letsch A, Stroux A, et al.: Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol 2006, 20;24:1910-1916.
• [21]Kimsey TF, Campbell AS, Albo D, Wilson M, Wang TN: Co-localization of macrophage inflammatory protein-3alpha (Mip-3alpha) and its receptor, CCR6, promotes pancreatic cancer cell invasion. Cancer J 2004, 10:374-380.
• [22]Kleeff J, Kusama T, Rossi DL, Ishiwata T, Maruyama H, Friess H, et al.: Detection and localization of Mip-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer 1999, 81:650-657.
• [23]Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, et al.: In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 1999, 190:1417-1426.
• [24]Thomachot MC, driss-Vermare N, Massacrier C, Biota C, Treilleux I, Goddard S, et al.: Breast carcinoma cells promote the differentiation of CD34+ progenitors towards 2 different subpopulations of dendritic cells with CD1a(high)CD86(-)Langerin- and CD1a(+)CD86(+)Langerin+ phenotypes. Int J Cancer 2004, 110:710-720.
• [25]McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark JW: Reporting recommendations for tumor marker prognostic studies (REMARK). Breast Cancer Res Treat 2006, 100:229-235.
• [26]Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958, 53:457-481.
• [27]Ghadjar P, Loddenkemper C, Coupland SE, Stroux A, Noutsias M, Thiel E, et al.: Chemokine receptor CCR6 expression level and aggressiveness of prostate cancer. J Cancer Res Clin Oncol 2008, 134:1181-1189.
• [28]Vongsa RA, Zimmerman NP, Dwinell MB: CCR6 regulation of the actin cytoskeleton orchestrates human beta defensin-2- and CCL20-mediated restitution of colonic epithelial cells. J Biol Chem 2009, 284:10034-10045.
• [29]Muthuswamy R, Mueller-Berghaus J, Haberkorn U, Reinhart TA, Schadendorf D, Kalinski P: PGE2 transiently enhances DC expression of CCR7 but inhibits the ability of DCs to produce CCL19 and attract naive T cells. Blood 2010.
• [30]Treilleux I, Blay JY, driss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, et al.: Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 2004, 10:7466-7474.