Parathyroid Hormone-Related Peptide and Malignancy

Parathyroid hormone-related peptide (PTHrP) was originally isolated as a causal factor for hypercalcemia of malignancy (HM), one of the most frequent paraneoplastic syndromes. The association of hypercalcemia with malignancy was originally assumed to be the result of tumor invasion of bone with resultant osteolysis (1,2), but subsequent studies demonstrated an association of hypercalcemia with cancer, even when the tumor had not metastasized to bone. In a careful clinical analysis of a case of renal cell carcinoma with metastases, it was noted that hypercalcemia was associated with hypophosphatemia (3). It was therefore postulated, because lysis of bone should liberate both calcium and phosphate, that the tumor was producing a factor that was both hypercalcemic and phosphaturic, analogous to parathyroid hormone (PTH) (3). The concept arose that tumors might “ectopically” produce PTH, which is normally expressed only in the parathyroid gland. The term “pseudohypoparathyroidism” was therefore employed to describe a syndrome in which cancers had not metastasized to bone, but were associated with hypercalcemia and other PTH-like biochemical abnormalities (4). Certain biochemical alterations were, however, found to differ in primary hyperparathyroidism and “pseudohyperparathyroidism,” including a higher level of serum calcium in the latter and a tendency in the latter toward an alkalosis rather than an acidosis. The development of sensitive bioassays for PTH-like bioactivity confirmed the presence of PTH-like material Parathyroid Hormone-Related Peptide and Malignancy