A hypercalcemic nude rat model that completely mimics human syndrome of humoral hypercalcemia of malignancy.

Tumors causing humoral hypercalcemia of malignancy (HHM) were implanted to athymic nude rats. In one of these rat models transplanted with uterine cancer (UCC), a complete reproduction of human HHM syndrome was achieved: hypercalcemia, hypophosphatemia with increased urinary phosphate and cyclic AMP excretion, and suppressed serum 1,25-dihydroxy-vitamin D (1,25(OH)2D) level. In another hypercalcemic nude rat model implanted with oral cavity cancer (OCC), all the features were similar except for markedly elevated serum 1,25(OH)2D. Hypercalcemia disappeared by surgical removal of the tumors in both models, confirming the humoral mechanisms for causing these features. Furthermore, in UCC tumor-bearing rats, hypophosphatemia, increased renal phosphate excretion, and reduced serum 1,25(OH)2D concentration were already present when these rats were only marginally hypercalcemic. These results raise the possibility that the changes in renal tubular phosphate handling and vitamin D metabolism in HHM are not secondary to hypercalcemia but are due to direct effects of the humoral factor(s) that cause this syndrome. Extracts of both tumors exhibited stimulation of cyclic AMP production in osteoblastlike cells, UMR 106, which could be almost completely inhibited by parathyroid hormone (PTH) antagonist, human PTH(3-34). By comparing the nature and characteristics of humoral factor(s) from UCC and OCC models, mechanisms responsible for causing these abnormalities can be explored. Thus, these nude rat models can be useful for elucidating the underlying mechanism of the development of HHM.