Parathyroid hormone-related protein and hypercalcemia.

The discovery of parathyroid hormone-related protein (PTH-rP) arose from interest in the mechanisms by which certain cancers cause hypercalcemia without necessarily metastasizing to bone. The humoral hypercalcemia of malignancy (HHM) had for a long time been ascribed to inappropriate production of parathyroid hormone (PTH) by cancers. The amino-terminal portions of PTH-rP and PTH have essentially identical actions through a common receptor for PTH/PTH-rP: to elevate plasma calcium by promoting bone resorption and decreasing calcium excretion. Assays for plasma PTH-rP fail to detect protein convincingly in normal plasma, but measurable levels have been found in up to 100% of patients with HHM, in 75% of patients with breast carcinoma metastatic to bone, and in some hypercalcemic patients with miscellaneous cancers. Whereas PTH-rP clearly functions as a hormone in those cancers in which it is produced in excess, in normal circumstances it is produced locally in many tissues in which it is a paracrine effector. There appears to be little doubt that PTH-rP is the major mediator of hypercalcemia in patients with HHM, although it is possible that other factors (e.g., bone resorbing cytokines) also could contribute in some patients. In the case of breast carcinoma, another possible role arises for PTH-rP. The high incidence of PTH-rP production by primary breast carcinomas, elevated plasma levels in 60% of those with hypercalcemia and lytic metastases, and higher incidence of PTH-rP production in skeletal versus those with nonskeletal metastases have led to the hypothesis that PTH-rP might contribute to breast carcinoma growth in bone. Experimental evidence currently is available to support this hypothesis. The discovery of PTH-rP has contributed greatly to current understanding of the skeletal complications of cancer.