Hypercalcemia is a common and life-threatening complication of cancer. In patients with solid tumors, the occurance of hypercalcemia without skeletal metastases suggests that a humoral mediator is responsible. Considerable evidence supports the proposal that this mediator is a tumor product that mimics parathyroid hormone (PTH) by activating the same receptor, although it is a distinct gene product. Such proteins are characteristically present in both conditioned culture medium and extracts of solid tumors causing hypercalcemia. Increases in the level of bioactive PTH in serum and of nephrogenous cyclic AMP and phosphate in the urine of hypercalcemic patients suggest that such PTH-like proteins have humoral effects. We have obtained evidence that after considerable purification, a PTH-like protein from human renal carcinoma cells retains direct bone-resorbing effects. We propose to complete the purification of this protein, determine whether it directly causes hypercalcemia, and develop a radioimmunoassay to detect it in serum and tumor extracts. Together, these results will critically test the hypothesis that a PTH-like protein is the mediator of hypercalcemia secreted by solid tumors. The physiologic role of a PTH-like protein will be clarified by studies of cultured keratinocytes, which have recently been shown to secrete a protein that is indistinguishable from the tumor product. In breast cancer, skeletal metastases characteristically precede the development of hypercalcemia, indicating that accelerated bone resorption has a local cause. We hypothesize that a transforming growth factor (TGF-Alpha) is a local mediator of the skeletal effects of breast carcinoma; others have suggested it also has humoral effects when secreted by other tumors. We will use a panel of specific antagonists to determine whether bone resorption produced by breast or other solid tumor cells is mediated by TGF-Alpha. These studies will provide a basis for the understanding, and ultimately the treatment, of hypercalcemia in malignancy.
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