Vivian Grill

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. Cancer 1997; 80:1564‐71.

Parathyroid hormone-related protein: a possible endocrine function in lactation

OBJECTIVE Parathyroid hormone‐related protein (PTHrP), initially discovered as the factor responsible for the syndrome of humoral hypercalcaemia of malignancy, has also been found to be expressed in placenta, in pregnant uterus, in the fetus at many locations, and in the lactating mammary gland. This study sought to establish whether PTHrP reaches the maternal circulation when it is expressed in mammary tissue during lactation or in the maternal reproductive tract during gestation.

Hypercalcemia of Malignancy

Prevalence Hypercalcemia is one of the most common metabolic complications of malignancy, developing in 3±30% of patients with cancer at some time during the course of their disease. Indeed malignancy is the most frequent cause of hypercalcemia in a general hospital patient population, whereas primary hyperparathyroidism is a more common cause of elevated blood calcium in the community at large. The incidence of hypercalcemia varies with the type of tumor. Primary tumors of lung, breast, head and neck, kidney and ovary have a higher incidence of hypercalcemia. Hypercalcemia occurs most typically with squamous cell carcinoma of the lung despite the fact that adenocarcinoma and small cell carcinoma frequently metastasize to bone. Hypercalcemia occurs in 30±40% of patients with malignant tumors of breast, but rarely in patients with colorectal cancers and prostate cancer. Hematological malignancies can be complicated by hypercalcemia which occurs in up to one third of patients with multiple myeloma. Primary bone tumors such as osteogenic sarcoma virtually never produce hypercalcemia. The association of speci®c tumors with hypercalcemia is related to their ability to secrete a factor which acts systemically and/or to their ability to metastasize to bone. This will be the subject of further discussion in following sections.

Parathyroid Hormone-Related Protein mRNA and Protein Expression in Multiple Myeloma: A Case Report

Multiple myeloma frequently leads to complications, such as osteolytic lesions, hypercalcemia, and pathological fractures. Increased bone resorption in myeloma is due to osteoclast activation. The nature of the osteoclast activator(s) remains unclear. We describe a case of multiple myeloma with marked hypercalcemia and skeletal complications that progressed rapidly despite chemotherapy. The patient had marked hypercalcemia at diagnosis (4.5 mmol/l), and elevated parathyroid hormone‐related protein (PTHrP) levels were found in plasma. Analysis of the bone marrow trephine biopsy showed PTHrP gene transcription and protein in myeloma cells. These results provide strong evidence for the production of significant amounts of PTHrP by human myeloma cells. PTHrP has been measured as elevated in the plasma of patients with myeloma and might be an important contributor to the skeletal complications in this disease.