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Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Low CCL17 expression associates with unfavorable postoperative prognosis of patients with clear cell renal cell carcinoma

Authors: Ying Xiong, Li Liu, Yu Xia, Jiajun Wang, Wei Xi, Qi Bai, Yang Qu, Jiejie Xu, Jianming Guo

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Chemokine (C–C motif) ligand 17 (CCL17) is a chemokine mainly produced by myeloid dendritic cells. It is a ligand for CC chemokine receptor 4 (CCR4) and CC chemokine receptor 8 (CCR8). The aim of this study was to investigate prognostic values of CCL17 expression in patients with clear cell renal cell carcinoma (ccRCC).

Methods

The study included 286 patients with ccRCC. CCL17 expression was analyzed by immunohistochemistry on tissue microarrays. Prognostic values of CCL17 expression and patients’ clinical outcomes were evaluated.

Results

Kaplan-Meier method showed that low CCL17 expression was associated with worse patient overall survival (OS) and recurrence-free survival (RFS) (OS, P = 0.002; RFS, P = 0.007). Low CCL17 expression was an adverse independent risk factor for OS and RFS in multivariate analyses (OS, P = 0.006, P = 0.011 for bootstrap; RFS, P = 0.002, P = 0.025 for bootstrap). We constructed two nomograms incorporating parameters derived from multivariate analyses to predict patients’ OS and RFS (OS, c-index 0.799; RFS, c-index 0.787) and they performed better than existed integrated models.

Conclusion

Low CCL17 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy. Established nomograms based on this information could help predict ccRCC patients’ OS and RFS.
Appendix
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Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
2.
go back to reference Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24.CrossRefPubMed Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24.CrossRefPubMed
3.
go back to reference Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34(3):193–205.CrossRefPubMed Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34(3):193–205.CrossRefPubMed
4.
go back to reference Meskawi M, Sun M, Trinh QD, Bianchi M, Hansen J, Tian Z, Rink M, Ismail S, Shariat SF, Montorsi F, et al. A review of integrated staging systems for renal cell carcinoma. Eur Urol. 2012;62(2):303–14.CrossRefPubMed Meskawi M, Sun M, Trinh QD, Bianchi M, Hansen J, Tian Z, Rink M, Ismail S, Shariat SF, Montorsi F, et al. A review of integrated staging systems for renal cell carcinoma. Eur Urol. 2012;62(2):303–14.CrossRefPubMed
5.
7.
go back to reference Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O. The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J Biol Chem. 1997;272(23):15036–42.CrossRefPubMed Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O. The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J Biol Chem. 1997;272(23):15036–42.CrossRefPubMed
8.
go back to reference Kumai T, Nagato T, Kobayashi H, Komabayashi Y, Ueda S, Kishibe K, Ohkuri T, Takahara M, Celis E, Harabuchi Y. CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer Immunol Immunother. 2015;64(6):697–705.CrossRefPubMedPubMedCentral Kumai T, Nagato T, Kobayashi H, Komabayashi Y, Ueda S, Kishibe K, Ohkuri T, Takahara M, Celis E, Harabuchi Y. CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer Immunol Immunother. 2015;64(6):697–705.CrossRefPubMedPubMedCentral
9.
go back to reference Real E, Kaiser A, Raposo G, Amara A, Nardin A, Trautmann A, Donnadieu E. Immature dendritic cells (DCs) use chemokines and intercellular adhesion molecule (ICAM)-1, but not DC-specific ICAM-3-grabbing nonintegrin, to stimulate CD4+ T cells in the absence of exogenous antigen. J Immunol. 2004;173(1):50–60.CrossRefPubMed Real E, Kaiser A, Raposo G, Amara A, Nardin A, Trautmann A, Donnadieu E. Immature dendritic cells (DCs) use chemokines and intercellular adhesion molecule (ICAM)-1, but not DC-specific ICAM-3-grabbing nonintegrin, to stimulate CD4+ T cells in the absence of exogenous antigen. J Immunol. 2004;173(1):50–60.CrossRefPubMed
10.
go back to reference Semmling V, Lukacs-Kornek V, Thaiss CA, Quast T, Hochheiser K, Panzer U, Rossjohn J, Perlmutter P, Cao J, Godfrey DI, et al. Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol. 2010;11(4):313–20.CrossRefPubMed Semmling V, Lukacs-Kornek V, Thaiss CA, Quast T, Hochheiser K, Panzer U, Rossjohn J, Perlmutter P, Cao J, Godfrey DI, et al. Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol. 2010;11(4):313–20.CrossRefPubMed
11.
go back to reference Henry CJ, Ornelles DA, Mitchell LM, Brzoza-Lewis KL, Hiltbold EM. IL-12 produced by dendritic cells augments CD8+ T cell activation through the production of the chemokines CCL1 and CCL17. J Immunol. 2008;181(12):8576–84.CrossRefPubMedPubMedCentral Henry CJ, Ornelles DA, Mitchell LM, Brzoza-Lewis KL, Hiltbold EM. IL-12 produced by dendritic cells augments CD8+ T cell activation through the production of the chemokines CCL1 and CCL17. J Immunol. 2008;181(12):8576–84.CrossRefPubMedPubMedCentral
12.
go back to reference Kim SP, Alt AL, Weight CJ, Costello BA, Cheville JC, Lohse C, Allmer C, Leibovich BC. Independent validation of the 2010 American Joint Committee on Cancer TNM classification for renal cell carcinoma: results from a large, single institution cohort. J Urol. 2011;185(6):2035–9.CrossRefPubMed Kim SP, Alt AL, Weight CJ, Costello BA, Cheville JC, Lohse C, Allmer C, Leibovich BC. Independent validation of the 2010 American Joint Committee on Cancer TNM classification for renal cell carcinoma: results from a large, single institution cohort. J Urol. 2011;185(6):2035–9.CrossRefPubMed
13.
go back to reference Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J, Egevad L, Algaba F, Moch H, Grignon DJ, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37(10):1490–504.CrossRefPubMed Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J, Egevad L, Algaba F, Moch H, Grignon DJ, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37(10):1490–504.CrossRefPubMed
14.
go back to reference Zisman A, Pantuck AJ, Wieder J, Chao DH, Dorey F, Said JW, de Kernion JB, Figlin RA, Belldegrun AS. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002;20(23):4559–66.CrossRefPubMed Zisman A, Pantuck AJ, Wieder J, Chao DH, Dorey F, Said JW, de Kernion JB, Figlin RA, Belldegrun AS. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002;20(23):4559–66.CrossRefPubMed
15.
go back to reference Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;97(7):1663–71.CrossRefPubMed Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;97(7):1663–71.CrossRefPubMed
16.
go back to reference Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol. 2002;168(6):2395–400.CrossRefPubMed Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol. 2002;168(6):2395–400.CrossRefPubMed
17.
go back to reference Pan D, Xu L, Liu H, Zhang W, Zhu Y, Xu J, Gu J. Interleukin-11 receptor predicts post-operative clinical outcome in patients with early-stage clear-cell renal cell carcinoma. Jpn J Clin Oncol. 2015;45(2):202–9.CrossRefPubMed Pan D, Xu L, Liu H, Zhang W, Zhu Y, Xu J, Gu J. Interleukin-11 receptor predicts post-operative clinical outcome in patients with early-stage clear-cell renal cell carcinoma. Jpn J Clin Oncol. 2015;45(2):202–9.CrossRefPubMed
18.
go back to reference Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–9.CrossRefPubMed Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–9.CrossRefPubMed
19.
go back to reference Meira-Machado L, Cadarso-Suarez C, Gude F, Araujo A. smoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors. Comput Math Methods Med. 2013;2013:745742.CrossRefPubMedPubMedCentral Meira-Machado L, Cadarso-Suarez C, Gude F, Araujo A. smoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors. Comput Math Methods Med. 2013;2013:745742.CrossRefPubMedPubMedCentral
20.
go back to reference Altman DG, Lausen B, Sauerbrei W, Schumacher M. Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst. 1994;86(11):829–35.CrossRefPubMed Altman DG, Lausen B, Sauerbrei W, Schumacher M. Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst. 1994;86(11):829–35.CrossRefPubMed
21.
go back to reference Bernardini G, Hedrick J, Sozzani S, Luini W, Spinetti G, Weiss M, Menon S, Zlotnik A, Mantovani A, Santoni A, et al. Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor. Eur J Immunol. 1998;28(2):582–8.CrossRefPubMed Bernardini G, Hedrick J, Sozzani S, Luini W, Spinetti G, Weiss M, Menon S, Zlotnik A, Mantovani A, Santoni A, et al. Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor. Eur J Immunol. 1998;28(2):582–8.CrossRefPubMed
22.
go back to reference Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998;187(6):875–83.CrossRefPubMedPubMedCentral Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998;187(6):875–83.CrossRefPubMedPubMedCentral
23.
go back to reference Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci. 2006;97(11):1139–46.CrossRefPubMed Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci. 2006;97(11):1139–46.CrossRefPubMed
24.
go back to reference Zhu F, Li X, Chen S, Zeng Q, Zhao Y, Luo F. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol. 2016;33(2):17.CrossRefPubMed Zhu F, Li X, Chen S, Zeng Q, Zhao Y, Luo F. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol. 2016;33(2):17.CrossRefPubMed
25.
go back to reference Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012;18(8):1254–61.CrossRefPubMed Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012;18(8):1254–61.CrossRefPubMed
26.
go back to reference Weide B, Allgaier N, Hector A, Forschner A, Leiter U, Eigentler TK, Garbe C, Hartl D. Increased CCL17 serum levels are associated with improved survival in advanced melanoma. Cancer Immunol Immunother. 2015;64(9):1075–82.CrossRefPubMed Weide B, Allgaier N, Hector A, Forschner A, Leiter U, Eigentler TK, Garbe C, Hartl D. Increased CCL17 serum levels are associated with improved survival in advanced melanoma. Cancer Immunol Immunother. 2015;64(9):1075–82.CrossRefPubMed
27.
go back to reference Ness TL, Ewing JL, Hogaboam CM, Kunkel SL. CCR4 is a key modulator of innate immune responses. J Immunol. 2006;177(11):7531–9.CrossRefPubMed Ness TL, Ewing JL, Hogaboam CM, Kunkel SL. CCR4 is a key modulator of innate immune responses. J Immunol. 2006;177(11):7531–9.CrossRefPubMed
28.
29.
go back to reference Weber C, Meiler S, Doring Y, Koch M, Drechsler M, Megens RT, Rowinska Z, Bidzhekov K, Fecher C, Ribechini E, et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011;121(7):2898–910.CrossRefPubMedPubMedCentral Weber C, Meiler S, Doring Y, Koch M, Drechsler M, Megens RT, Rowinska Z, Bidzhekov K, Fecher C, Ribechini E, et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011;121(7):2898–910.CrossRefPubMedPubMedCentral
30.
go back to reference Heiseke AF, Faul AC, Lehr HA, Forster I, Schmid RM, Krug AB, Reindl W. CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cell-mediated protection from colitis. Gastroenterology. 2012;142(2):335–45.CrossRefPubMed Heiseke AF, Faul AC, Lehr HA, Forster I, Schmid RM, Krug AB, Reindl W. CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cell-mediated protection from colitis. Gastroenterology. 2012;142(2):335–45.CrossRefPubMed
Metadata
Title
Low CCL17 expression associates with unfavorable postoperative prognosis of patients with clear cell renal cell carcinoma
Authors
Ying Xiong
Li Liu
Yu Xia
Jiajun Wang
Wei Xi
Qi Bai
Yang Qu
Jiejie Xu
Jianming Guo
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3106-y

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