Evidence That the Bone Resorption-stimulating Factor Produced by Mouse Fibrosarcoma Cells is Prostaglandin E 2 . A New Model for the Hypercalcemia of Cancer

A transplantable mouse fibrosarcoma, HSDM(1), produces a potent bone resorption-stimulating factor. The factor can be extracted from the tumor tissue and harvested from the medium of clonal strains of HSDM(1) tumor cells growing in monolayer culture. It has several chemical and biological properties of a prostaglandin. Using radioimmunoassay techniques, we have shown that HSDM(1) cells synthesize and secrete large quantities of prostaglandin E(2) (PGE(2)). The specific bone resorption-stimulating activity of the HSDM(1) factor extracted from the tumor is high and approximately equal to that of PGE(2) as measured in a bone tissue culture system in vitro. Indomethacin, a potent inhibitor of PGE(2) synthesis in HSDM(1) cells, also inhibits production by the cells of the bone resorption-stimulating factor, and has no detectable nonspecific effects on the bone culture assay system. Mice bearing the HSDM(1) tumor have higher levels of both calcium and PGE(2) in serum than control mice. We conclude that PGE(2) is the bone resorption-stimulating factor produced by HSDM(1) tumor cells, and that secretion of PGE(2) by the tumor in vivo accounts for the relative hypercalcemia observed in tumor-bearing animals. The HSDM(1) tumor cell system constitutes a new model for studying the pathogenesis of hypercalcemia associated with certain malignant tumors.