Pathogenesis of humoral hypercalcemia of malignancy.

The three biologic activities most commonly associated with tumors that produce Humoral Hypercalcemia of Malignancy (HHM) include; 1) adenylate cyclase stimulating activity (PTH-like activity), 2) in vitro bone resorbing activity, and 3) transforming growth factor activity. The canine adenocarcinoma (CAC-8) model of HHM contains all three activities and the first two are inhibited by a PTH receptor antagonist. These data in light of the recent purification of PTH-related peptides from human tumors suggest that CAC-8 produces a PTH-related protein that is important in the pathogenesis of hypercalcemia. The CAC-8 tumor is a well characterized example of HHM and offers several advantages for further investigations on the pathogenesis of HHM: 1) transplantable tumor line from a spontaneous neoplasm in the dog, 2) tumor extracts contain the three biologic activities associated with HHM, 3) slow progressive growth rate in nude mice permits investigations on treatment of HHM, 4) increased bone resorption and formation in nude mice mimics the effects of PTH on bone, and 5) the only model of HHM that has been demonstrated to contain bone resorbing activity that can be inhibited by a PTH receptor antagonist.