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

Abstract

The role of interleukin-6 in the induction of hypercalcemia in renal cell carcinoma transplanted into nude mice Weissglas, M.G.; Schamhart, D.H.J.; Lowik, C; Papapoulos, S.; Theuns, H.; Kurth, K-H. Published in: Endocrinology DOI:10.1210/en.138.5.1879 Link to publication Citation for published version (APA):Weissglas, M. G., Schamhart, D. H. J., Lowik, C., Papapoulos, S., Theuns, H., & Kurth, K-H. (1997). The role of interleukin-6 in the induction of hypercalcemia in renal cell carcinoma transplanted into nude mice. Endocrinology, 138, 1879-1885. DOI: 10.1210/en.138.5.1879 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. ABSTRACTHypercalcemia 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 mm 3 ), that in RC-9 was 81 pg/ml (TV, 1800 mm 3 ), and that in NC-65 was 2368 pg/ml (TV, 1800 mm 3 ). 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 growthinhibit...

Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding

“…In contrast, tumors continued to grow in control mice that were injected with physiological saline without endostatin ( Figure 7A). The RC-9 tumor produces interleukin-6 and parathyroid hormone-like protein (PTHrP) and therefore causes hypercalcemia and hypophosphatemia (Weissglas et al, 1995(Weissglas et al, , 1997. As expected, when serum levels of calcium and phosphate were determined at the end of the experiment, endostatin-treated animals had lower calcium levels and higher phosphate levels than animals in the control group ( Figure 7B and C).…”

Production of parathyroid hormone‐related protein in two new cell lines of renal cell carcinoma

“…26 Weissglas et al suggested that IL-6 might have enhanced hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting renal carcinomas. 12 This is not in agreement with the present study, in which the SMRC-3 cell line produced more IL-6 and grew faster than SMRC-1 but turned out to secrete less PTHrP. These findings suggest that IL-6 promoted tumor growth by a non-selective autocrine mechanism.…”

“…Parathyroid hormone-related protein has been reported to be released in some new cell lines of human kidney and lung cancer in culture. 12,13 However, the patients from whom these cell lines have been isolated have not necessarily presented with hypercalcemia and the contribution of PTHrP to calcium homeostasis in the tumors remains to be elucidated.…”

Renal Cell Carcinoma Presenting with Paraneoplastic Hypercalcemic Coma: A Case Report and Review of the Literature

“…Some studies suggest that IL-6 stimulates tumor growth. 34,35 It is not clear whether this cytokine causes hypercalcemia either directly or indirectly by increasing the effect of PTHrP on bone resorption. [36][37][38] At this time, IL-6-mediated hypercalcemia appears to be multifactorial.…”