HYPERCALCEMIA AND COSECRETION OF INTERLEUKIN-6 AND PARATHYROID-HORMONE RELATED PEPTIDE BY A HUMAN RENAL-CELL CARCINOMA IMPLANTED INTO NUDE-MICE

Humoral hypercalcemia of malignancy is a paraneoplastic syndrome belie ved to be due to production by the tumor of substances that stimulate osteoclastic bone resorption primarily. The human renal cell carcinoma cell line RC-8, grown in nude mice, was investigated for factors invo lved in renal cancer-induced hypercalcemia. At a tumor load of 200 to 400 mm.(3) the mice developed hypercalcemia and hypophosphatemia assoc iated with a rise in serum 1,25-dihydroxyvitamin D concentration and c achexia. The tumor released 1) significant amounts of human interleuki n-6 (IL-6) and 2) parathyroid hormone-related peptide (PTHrP) into the circulation. Cancer cells further expressed mRNA for both human IL-6 and PTHrP. No secretion of human tumor necrosis factor-a or interleuki n-1 beta could be demonstrated in the circulation of the host. Antibod ies to IL-6 caused a significant (p = 0.043) inhibition of tumor growt h and decreased serum calcium concentrations compared with control ani mals. Our data suggest that IL-6 is involved, either directly or indir ectly, in the development of hypercalcemia in renal cell carcinoma.