Copurification of Osteolytic and Transforming Growth Factor β Activities Produced by Human Lung Tumor Cells Associated with Humoral Hypercalcemia of Malignancy

The SK-Luci-6 cell line, established from a large-cell anaplastic lung tumor of a patient with humoral hypercalcemia of malignancy (HHM), was investigated to identify osteolytic factors produced that might mediate HHM. Most HHM-associated tumors are thought to produce parathyroid hormone-related proteins or transforming growth factor (TGF) α. SK-Luci-6 cells formed s.c. tumors and induced hypercalcemia in athymic nude mice. Serum-free conditioned medium from SK-Luci-6 cultures induced bone resorption in neonatal mouse calvariae in vitro, and also contained TGF-β activity and mitogenic activity. SK-Luci-6 cell conditioned medium did not displace [125I]epidermal growth factor binding to cell receptors or stimulate cyclic AMP formation in rat osteosarcoma cells, suggesting that the conditioned medium did not contain TGF-α or parathyroid hormone-related proteins. The osteolytic, TGF-β, and mitogenic activities copurified in several chromatographic separations: gel filtration in acid and then in guanidine HC1; ion exchange; and reverse phase. The results suggest that in the HHM-associated SK-Lud-6 tumor, the causative osteolytic factor produced by the tumor cells is not a parathyroid hormone-related protein or TGF-α but, rather, may be a TGF-β.