Humoral hypercalcemia of malignancy. Release of a prostaglandin-stimulating bone-resorbing factor in vitro by human transitional-cell carcinoma cells.

Abstract

Secretion by tumor cells of circulating bone-resorbing factors may frequently underlie the hypercalcemia that occurs in patients with malignancy. Efforts to identify the responsible mediators have been hampered by a lack of available human tumor cell systems suitable for study of the pathogenesis of the humoral hypercalcemia syndrome. We have established a transitionalcell carcinoma (TCC) line in vitro from a patient with humoral hypercalcemia. These cells are tumorigenic and cause hypercalcemia in athymic nude mice. Culture medium conditioned by TCC cells contains potent bone-resorbing activity in vitro, the physical and biological properties of which are similar to those of bone-resorbing activity present in the original patient's urine. The bone-resorbing activity of the TCC factor is accompanied by increased prostaglandin release from bone and is blocked by indomethacin and calcitonin. The TCC-derived bone-resorbing activity coelutes with prostaglandin-stimulating activity during gel filtration with an approximate molecular weight of 15,000. This activity is nondialyzable, stable to concentrated urea and reducing agents, and destroyed by boiling. The TCC factor does not increase cyclic AMP production in bone or kidney bioassays and does not exhibit transforming growth factor activity. We conclude that a unique macromolecular factor released by TCC cells causes bone resorption by a mechanism dependent upon stimulation of bone cell cyclooxygenase, and that this factor is the probable cause of the hypercalcemia in vivo. The TCC cell line provides a new model for study of the human humoral hypercalcemia syndrome.

Hypercalcemia in breast cancer

“…In this case, indomethacin was effective in decreasing serum calcium concentrations [47]. Bringhurst et al [15] reported that a cancer cell line derived from a transitional cell carcinoma produced a factor stimulating PGE2 release from bone, which in turn induced bone resorption. The effect of this factor was blocked by indomethacin and calcitonin [15,16,48,49].…”

“…PGE2 is a potent stimulant of osteoclastic bone resorption [13,15] although it was not considered among the humoral factors responsible for hypercalcemia, because of its local origin and action. Circulating PGE2 is responsible for hypercalcemia in animal models [45,46].…”

“…The nature of these humoral factors has yet to be fully defined, but recent evidence suggests that parathyroid hormone-related protein (PTHrP), prostaglandin E 2 (PGE2) , interleukin-1 (IL-1) and growth factors (GFs) may be involved. These factors may be secreted by remote tumor tissue or released locally by metastatic cells [13][14][15][16][17][18][19][20][21]. Another possible mechanism of hypercalcemia could be that tumoral cells are able to resorb bone directly, independently of osteoclast stimulation and release of humoral factors [3,6,22].…”

The Tumor Cells (FA-6) Established from a Pancreatic Cancer Associated with Humoral Hypercalcemia of Malignancy: A Simultaneous Production of Parathyroid Hormone-Like Activity and Transforming Growth Factor Activity.

“…Although various animal (Sica et al, 1983;D'Souza et al, 1984;Rosol et al, 1986) and human (Strewler et al, 1983;Bringhurst et al, 1986;Nissenson et al, 1985;Sato et al, 1987a, b) tumor cells associated with HHM have been cultured, cells originating in exocrine pancreatic cancer have not been established in vitro. In the present study, tumor cells were selected from an undifferentiated pleomorphic adenocarcinoma of exocrine pancreas associated with HHM which was injected into nude mice and re- Albumin (66 kDa), carbonic anhydrase (29 kDa), cytochrome C (12.4 kDa), and aprotinin (6.5 kDa) were used as markers of mole;ular size.…”

Production of parathyroid hormone-related protein in tumour xenografts in nude mice presenting with hypercalcaemia

“…Since TGF-x possesses bone-resorbing activity (Tashjian et al, 1986), this growth factor could aggravate PTHrP-induced hypercalcaemia in this case. There are a number of compounds with bone-resorbing activity including prostaglandins, TGF-P, epidermal growth factor, interleukin-la and -1p (Bringhurst et al, 1986;Tashjian et al, 1986;Linkhart et al, 1989;Sato et al, 1987;Mundy, 1988). Examination of the production of these compounds in these transplantable tumours is necessary to better understand their potential roles in this morbidity in these animal models.…”