Abstract
AIMS: Interleukin 6 (IL-6) is expressed in the majority of renal cell carcinomas and has an important role in the proliferation of some renal cell carcinoma cell lines. This action is mediated by two membrane proteins, gp80 (the IL-6 receptor; IL-6R), which binds IL-6, and gp130, which transduces the signal. The soluble form of gp80 (sIL-6R) is able to activate gp130 when complexed to the IL-6 molecule. These considerations prompted an investigation of IL-6R expression in this malignancy. IL-6, C reactive protein (CRP), and sIL-6R were also measured in serum and correlated to clinical and pathological features. METHODS: Immunostaining was performed on cryostat sections from renal cell carcinoma tumours with M91, an anti-IL-6R monoclonal antibody, using the alkaline phosphatase antialkaline phosphatase technique. The proliferation index was measured using the KI-67 monoclonal antibody. CRP, IL-6, and sIL-6R were measured in serum before nephrectomy, using an immunoenzymatic or immunoradiometric assay. RESULTS: There were significant differences in survival in patients with tumours larger than 8 cm, metastasis at diagnosis, high nuclear grade tumours, detectable serum concentrations of IL-6 (correlated to CRP serum concentration), more than 4% proliferating cells, and the presence of the IL-6R in situ. Furthermore, the serum IL-6 concentration correlated with tumour size and stage. The mean serum sIL-6R concentration was not significantly different from that observed in 40 normal subjects. Tumour IL-6R expression was present in 10 samples. There was a significant association between the presence of the IL-6 receptor in tumours and tumour stage, nuclear grade, proliferation index, and serum IL-6. CONCLUSIONS: This study revealed the importance of IL-6/CRP and IL-6R expression in situ as potential new prognostic factors and opens the way to new therapeutic strategies in renal cell carcinoma.
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- Bataille R., Boccadoro M., Klein B., Durie B., Pileri A. C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system. Blood. 1992 Aug 1;80(3):733–737. [PubMed] [Google Scholar]
- Blay J. Y., Favrot M., Rossi J. F., Wijdenes J. Role of interleukin-6 in paraneoplastic thrombocytosis. Blood. 1993 Oct 1;82(7):2261–2262. [PubMed] [Google Scholar]
- Blay J. Y., Negrier S., Combaret V., Attali S., Goillot E., Merrouche Y., Mercatello A., Ravault A., Tourani J. M., Moskovtchenko J. F. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res. 1992 Jun 15;52(12):3317–3322. [PubMed] [Google Scholar]
- Fuhrman S. A., Lasky L. C., Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982 Oct;6(7):655–663. doi: 10.1097/00000478-198210000-00007. [DOI] [PubMed] [Google Scholar]
- Gaillard J. P., Bataille R., Brailly H., Zuber C., Yasukawa K., Attal M., Maruo N., Taga T., Kishimoto T., Klein B. Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol. 1993 Apr;23(4):820–824. doi: 10.1002/eji.1830230408. [DOI] [PubMed] [Google Scholar]
- Guinan P. D., Vogelzang N. J., Fremgen A. M., Chmiel J. S., Sylvester J. L., Sener S. F., Imperato J. P. Renal cell carcinoma: tumor size, stage and survival. Members of the Cancer Incidence and End Results Committee. J Urol. 1995 Mar;153(3 Pt 2):901–903. [PubMed] [Google Scholar]
- Hirata Y., Taga T., Hibi M., Nakano N., Hirano T., Kishimoto T. Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies. J Immunol. 1989 Nov 1;143(9):2900–2906. [PubMed] [Google Scholar]
- Kishimoto T., Akira S., Narazaki M., Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995 Aug 15;86(4):1243–1254. [PubMed] [Google Scholar]
- Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
- Klein B., Zhang X. G., Jourdan M., Content J., Houssiau F., Aarden L., Piechaczyk M., Bataille R. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood. 1989 Feb;73(2):517–526. [PubMed] [Google Scholar]
- Kyrtsonis M. C., Dedoussis G., Zervas C., Perifanis V., Baxevanis C., Stamatelou M., Maniatis A. Soluble interleukin-6 receptor (sIL-6R), a new prognostic factor in multiple myeloma. Br J Haematol. 1996 May;93(2):398–400. doi: 10.1046/j.1365-2141.1996.4721018.x. [DOI] [PubMed] [Google Scholar]
- Liautard J., Gaillard J. P., Mani J. C., Montero-Julian F., Duperray C., Lu Z. Y., Jourdan M., Klein B., Brailly H., Brochier J. Epitope analysis of human IL-6 receptor gp80 molecule with monoclonal antibodies. Eur Cytokine Netw. 1994 May-Jun;5(3):293–300. [PubMed] [Google Scholar]
- Miki S., Iwano M., Miki Y., Yamamoto M., Tang B., Yokokawa K., Sonoda T., Hirano T., Kishimoto T. Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett. 1989 Jul 3;250(2):607–610. doi: 10.1016/0014-5793(89)80805-1. [DOI] [PubMed] [Google Scholar]
- Morita R., Saito S., Ishikawa J., Ogawa O., Yoshida O., Yamakawa K., Nakamura Y. Common regions of deletion on chromosomes 5q, 6q, and 10q in renal cell carcinoma. Cancer Res. 1991 Nov 1;51(21):5817–5820. [PubMed] [Google Scholar]
- Müller-Newen G., Köhne C., Keul R., Hemmann U., Müller-Esterl W., Wijdenes J., Brakenhoff J. P., Hart M. H., Heinrich P. C. Purification and characterization of the soluble interleukin-6 receptor from human plasma and identification of an isoform generated through alternative splicing. Eur J Biochem. 1996 Mar 15;236(3):837–842. doi: 10.1111/j.1432-1033.1996.00837.x. [DOI] [PubMed] [Google Scholar]
- Nanus D. M., Lynch S. A., Rao P. H., Anderson S. M., Jhanwar S. C., Albino A. P. Transformation of human kidney proximal tubule cells by a src-containing retrovirus. Oncogene. 1991 Nov;6(11):2105–2111. [PubMed] [Google Scholar]
- Serve H., Steinhauser G., Oberberg D., Flegel W. A., Northoff H., Berdel W. E. Studies on the interaction between interleukin 6 and human malignant nonhematopoietic cell lines. Cancer Res. 1991 Aug 1;51(15):3862–3866. [PubMed] [Google Scholar]
- Seymour J. F., Talpaz M., Cabanillas F., Wetzler M., Kurzrock R. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol. 1995 Mar;13(3):575–582. doi: 10.1200/JCO.1995.13.3.575. [DOI] [PubMed] [Google Scholar]
- Sporeno E., Savino R., Ciapponi L., Paonessa G., Cabibbo A., Lahm A., Pulkki K., Sun R. X., Toniatti C., Klein B. Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. Blood. 1996 Jun 1;87(11):4510–4519. [PubMed] [Google Scholar]
- Stadler W. M., Richards J. M., Vogelzang N. J. Serum interleukin-6 levels in metastatic renal cell cancer: correlation with survival but not an independent prognostic indicator. J Natl Cancer Inst. 1992 Dec 2;84(23):1835–1836. doi: 10.1093/jnci/84.23.1835. [DOI] [PubMed] [Google Scholar]
- Tsukamoto T., Kumamoto Y., Miyao N., Masumori N., Takahashi A., Yanase M. Interleukin-6 in renal cell carcinoma. J Urol. 1992 Dec;148(6):1778–1782. doi: 10.1016/s0022-5347(17)37026-x. [DOI] [PubMed] [Google Scholar]
- Yasukawa K., Saito T., Fukunaga T., Sekimori Y., Koishihara Y., Fukui H., Ohsugi Y., Matsuda T., Yawata H., Hirano T. Purification and characterization of soluble human IL-6 receptor expressed in CHO cells. J Biochem. 1990 Oct;108(4):673–676. doi: 10.1093/oxfordjournals.jbchem.a123261. [DOI] [PubMed] [Google Scholar]
- Zbar B., Brauch H., Talmadge C., Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. 1987 Jun 25-Jul 1Nature. 327(6124):721–724. doi: 10.1038/327721a0. [DOI] [PubMed] [Google Scholar]
- Zhang X. G., Gaillard J. P., Robillard N., Lu Z. Y., Gu Z. J., Jourdan M., Boiron J. M., Bataille R., Klein B. Reproducible obtaining of human myeloma cell lines as a model for tumor stem cell study in human multiple myeloma. Blood. 1994 Jun 15;83(12):3654–3663. [PubMed] [Google Scholar]
- de Riese W. T., Crabtree W. N., Allhoff E. P., Werner M., Liedke S., Lenis G., Atzpodien J., Kirchner H. Prognostic significance of Ki-67 immunostaining in nonmetastatic renal cell carcinoma. J Clin Oncol. 1993 Sep;11(9):1804–1808. doi: 10.1200/JCO.1993.11.9.1804. [DOI] [PubMed] [Google Scholar]