CCR6 is expressed in various tumors and has been implicated in the process of tumor progression and metastasis. Its chemokine ligand, CCL20, is present in different tissues including lymph nodes, but also the normal prostate. This study was performed to investigate a potential relationship between CCR6 and CCL20 expression and features of human prostate cancer (PCA) at time of primary treatment.
Immunohistochemistry was used to detect CCR6 and CCL20 expression in archival tissue blocks of 80 PCA cases of various tumor grades and stages. Evaluation was semiquantitatively by visual scoring and quantitatively by digital image analysis (DIA). CCR6 and CCL20 expression was compared with Gleason score, stage, perineural invasion, nodal metastasis, age, and preoperative serum prostate-specific antigen (PSA) level by univariate and multivariate analyses.
Staining intensity of CCR6 in tumor cells varied considerably, with it being: weak in 21 tumors (26.2%), intermediate in 44 (55.0%), and strong in 15 (18.8%), with 3.6-log differences in DIA measurements. CCL20 expression was absent in eight tumors (10.0%), weak in 41 (51.2%), intermediate in 23 (28.8%), and strong in eight (10.0%). CCR6 and CCL20 expression did not correlate. CCR6 expression was associated with T-category (P < 0.0005), Gleason score (P = 0.003), and lymph node metastasis (P = 0.002).
Expression levels of CCR6 in PCA were associated with clinical and pathologic features of more advanced and aggressive prostate cancer. Thus, CCR6 may directly or indirectly be involved in tumor progression and should be evaluated as novel candidate target molecule for specific treatment interventions.
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Arya M, Patel HRH, Williamson M (2003) Chemokines: key players in cancer. Curr Med Res Opin 19:557–564
Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K, Nomiyama H, Yoshie O (1997) Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J Biol Chem 272:14893–14898
Brand S, Olszak T, Beigel F, Diebold J, Otte JM, Eichhorst ST, Göke B, Dambacher J (2006) Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signalling resulting in proliferation and migration of colorectal cancer cells. J Cell Biochem 97:709–723
Buri C, Gutersohn A, Hauser C, Kappeler A, Mueller C (2004) The chemokines CCL11, CCL20, CCL21, and CCL24 are preferentially expressed in polarized human secondary lymphoid follicles. J Pathol 204:208–216
Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 32:219–229
Fujii H, Itoh Y, Yamaguchi K, Yamauchi N, Harano Y, Nakajima T, Minami M, Okanoue T (2004) Chemokine CCL20 enhances the growth of HuH7 cells via phosphorylation of p44/42 MAPK in vitro. Biochem Biophys Res Commun 322:1052–1058
Ghadjar P, Coupland SE, Na IK, Noutsias M, Letsch A, Stroux A, Bauer S, Buhr HJ, Thiel E, Scheibenbogen C, Keilholz U (2006) Chemokine receptor CCR6 expression level and liver metastasis in colorectal cancer. J Clin Oncol 24:1910–1916
Gleason DF, Mellinger GT (1974) Prediction of prognosis for prostatic adenocarcinoma by combined histologic grading and clinical stage. J Urol 111:58–64
Hieshima K, Imai T, Opdenakker G, Van Damme J, Kusuda J, Tei H, Sakaki Y, Takatsuki K, Miura R, Yoshie O, Nomiyama H (1997) Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine (LARC) expressed in liver Chemotactic activity for lymphocytes and gene localization on chromosome 2. J Biol Chem 272:5846–5853
Hromas R, Gray PW, Chantry D, Godiska R, Krathwohl M, Fife K, Bell GI, Takeda J, Aronica S, Gordon M, Cooper S, Broxmeyer HE, Klemsz MJ (1997) Cloning and characterization of exodus, a novel β-chemokine. Blood 89:3315–3322
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30
Johnson Z, Schwarz M, Power CA, Wells TN, Proudfoot AE (2005) Multi-faceted strategies to combat disease by interference with the chemokine system. Trends Immunol 26:268–274
Kleeff J, Kusama T, Rossi DL, Ishiwata T, Maruyama H, Friess H, Büchler MW, Zlotnik A, Korc M (1999) Detection and localization of MIP-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer 81:650–657
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56
Murphy PM (2001) Chemokines and the molecular basis of cancer metastasis. N Engl J Med 345:833–835
Norton AJ, Jordan S, Yeomans P (1994) Brief, high-temperature heat denaturation (pressure cooking): a simple and effective method of antigen retrieval for routinely processed tissues. J Pathol 173:371–379
Noutsias M, Fechner H, de Jonge H, Wang X, Dekkers D, Houtsmuller AB, Pauschinger M, Bergelson J, Warraich R, Yacoub M, Hetzer R, Lamers J, Schultheiss HP, Poller W (2001) Human coxsackie–adenovirus receptor is colocalized with integrins alpha(v) beta(3) and alpha(v) beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: implications for cardiotropic viral infections. Circulation 104:275–280
Noutsias M, Pauschinger M, Ostermann K, Escher F, Blohm JH, Schultheiss H, Kuhl U (2002) Digital image analysis system fort the quantification of infiltrates and cell adhesion molecules in inflammatory cardiomyopathy. Med Sci Monit 8:MT59–MT71
Power CA, Church DJ, Meyer A, Alouani S, Proudfoot AE, Clark-Lewis I, Sozzani S, Mantovani A, Wells TN (1997) Cloning and characterization of a specific receptor for the novel cc chemokine MIP-3α from lung dendritic cells. J Exp Med 186:825–835
Rossi D, Zlotnik A (2000) The biology of chemokines and their receptors. Annu Rev Immunol 18:217–242
Rossi DL, Vicari AP, Franz-Bacon K, McClanahan TK, Zlotnik A (1997) Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3α and MIP3-β. J Immunol 158:1033–1036
Saitoh H, Hida M, Shimbo T, Nakamura K, Yamagata J, Satoh T (1984) Metastatic patterns of prostatic cancer. Correlation between sites and number of organs involved. Cancer 54:3078–3084
Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gönner U, Wilsberg V, Junginger T, Berger MR, Galle PR, Moehler M (2005) Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behaviour of human colorectal cancer. Clin Cancer Res 11:1743–1750
Schutyser E, Struyf S, Van Damme J (2003) The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev 14:409–426
Sobin LH, Wittekind CH (2002) The prostate. In: Sobin LH, Wittekind CH (eds) TNM classification of malignant tumors. Wiley, New York, pp 184–187
Uchida H, Iwashita Y, Sasaki A, Shibata K, Matsumoto T, Ohta M, Kitano S (2006) Chemokine receptor CCR6 as a prognostic factor after hepatic resection for hepatocellular carcinoma. J Gastroenterol Hepatol 21:161–168
Yoshie O, Imai T, Nomiyama H (2001) Chemokines in immunity. Adv Immunol 78:57–110
Zeelenberg IS, Ruuls-Van Stalle L, Roos E (2003) The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res 63:3833–3839
This study was supported by the Deutsche Forschungsgemeinschaft through the SFB TR 19, TPB2 to MN. We thank E. Berg and H. Protz for their excellent technical assistance.
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Ghadjar, P., Loddenkemper, C., Coupland, S.E. et al. Chemokine receptor CCR6 expression level and aggressiveness of prostate cancer. J Cancer Res Clin Oncol 134, 1181 (2008). https://doi.org/10.1007/s00432-008-0403-5
- Prostate cancer