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The Role of Interleukin-6 in the Induction of Hypercalcemia in Renal Cell Carcinoma Transplanted into Nude Mice

Departments of Urology (M.G.W.) and Endocrinology (C.W.G.M.L., S.E.P.), University Hospital Leiden, and the Division of Vascular and Connective Tissue Research, TNO-Prevention and Health (H.M.T.), Leiden; and the Department of Urology (D.H.J.S., K.-H.K.), University of Amsterdam, Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. M. G. Weissglas, University Hospital Leiden, Department of Urology, J3-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Hypercalcemia is a well known complication of renal cell carcinoma (RCC). As RCCs can produce IL-6, and IL-6 may stimulate bone resorption and cause mild hypercalcemia, we examined whether IL-6 is involved in renal cancer-associated hypercalcemia in vivo. Three human renal cell carcinoma tumor lines (RC-8, RC-9, and NC-65) growing in nude mice were studied. Tumors were implanted sc, and parameters of bone metabolism and serum human IL-6 levels were determined in relation to tumor volume (TV). All three tumor lines secreted human IL-6, although in different quantities. The maximum level of IL-6 in RC-8 was 434 pg/ml (TV, 200 mm³), that in RC-9 was 81 pg/ml (TV, 1800 mm³), and that in NC-65 was 2368 pg/ml (TV, 1800 mm³). Hypercalcemia developed in RC-8 and RC-9 tumor-bearing animals, but not in NC-65-bearing animals. The hypercalcemia in both RC-8 and RC-9 tumor lines was associated with elevated levels of PTH-related peptide (PTHrP) and loss of trabecular bone volume. Serum calcium and phosphate concentrations showed an almost linear relationship with plasma PTHrP independently of the tumor line and serum IL-6 levels. No hypercalcemia occurred in the NC-65 animals, which had the highest levels of IL-6, but no detectable plasma PTHrP and PTHrP messenger RNA expression in the tumor. Administration of neutralizing antibodies to IL-6 to RC-8 animals normalized serum calcium concentrations and PTHrP values and induced a significant inhibition of tumor growth. No such effect on tumor growth of anti-IL-6 was seen in the other two tumor lines. The normalization of serum calcium in RC-8 mice is most likely attributed to the growth-inhibiting effect of anti-IL-6 on RC-8 tumor. We conclude that IL-6 secreted by RCC does not contribute directly to hypercalcemia, but may enhance hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting carcinomas.

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