Tumor products and the hypercalcemia of malignancy.

Introduction One of the most interesting aspects of the hypercalcemia of malignancy is that it is unlikely that the hypercalcemia is due to the secretion by the tumor cells of one gene product which causes osteoclastic bone resorption and hypercalcemia, but rather that multiple tumor products work in concert on bone and kidney to overwhelm the normal compensatory mechanisms which guard calcium homeostasis so carefully. Moreover, although tumors secrete multiple factors which affect calcium metabolism, in the great majority of nonparathyroid gland tumors it is clear that parathyroid hormone itself is not one of these factors. Our understanding of the mechanisms of hypercalcemia of malignancy has advanced steadily over the last five years. This has occurred in part because of the application of the emerging techniques of molecular biology to this field. The use ofcomplementary DNA (cDNA) probes for detecting gene expression and the availability of recombinant tumor products for testing in biological assays have clarified some of the mechanisms by which tumors affect bone cell function. Moreover, investigators have realized that understanding the mechanisms of tumor-induced hypercalcemia may not only lead to increasing our knowledge of this important clinical problem, but since production of these factors by tumors probably represents aberrations of normal physiological mechanisms, clarification of their mode of action may lead to new insights into normal bone remodeling. Tumors associated with hypercalcemia of malignancy do not represent a homogeneous group, and there is no single unifying mechanism that can explain all cases of hypercalcemia. However, it is likely that similar mechanisms are responsible in similar types of tumors (1). In the hematologic malignancies ("15-20% of the total), local bone-resorbing factors are responsible for extensive osteolytic bone destruction and hypercalcemia usually occurs in association with impaired glomerular filtration. In a second group, the solid tumors associated with advanced osteolytic metastases, hypercalcemia rarely occurs unless the tumor is widespread and there is extensive local bone destruction. The most common example of this group is breast cancer (-25% of the total). A third group is comprised of solid tumors such as squamous cell carcinoma of the lung, head, and neck, carcinoma of the kidney, and carcinoma of the ovaries, where the primary mechanism is increased bone resorption caused by tumor secretion of a circulating stimulator or stimulators of osteoclast activity. This syndrome is called