Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells.

Abstract

A B S T R A C T The culture media of three cell lines, a human prostate carcinoma (PC3), a rat Leydig cell tumor (Rice-500), and a rat carcinosarcoma , that were derived from tumors associated with humoral hypercalcemia of malignancy (HHM), were examined for stimulation of adenylate cyclase in ROS 17/2.8 osteoblastic cells and for bone resorptive activity in culture. Cells from a nonhypercalcemic variant of the WRC 256 tumor served as control. Extracts from three solid human tumors, a lung adenocarcinoma from a patient with HHM and two adendcarcinomata from normnocalcemic patients (lung and colon), were also examined for adenylate cyclase stimulation. We found excellent correlation between stimulation of cyclic AMP accumulation in ROS 17/2.8 cells and bone resorbing activity in culture, or production of HHM in vivo. Stimulation of adenylate cyclase by HHM factors was inhibited by the parathyroid hormone competitive inhibitor, [8norleucyl, '8norleucyl, 34tyrosinyl] bovine parathyroid hormone (3-34) amide.

Hypercalcemia of malignancy revisited.

“…The only conclusion from these observations can be that renal tubular calcium reabsorption plays an important role in the pathophysiology of the humoral hypercalcemia in this model. This conclusion has been strengthened recently by observations that synthetic peptides of PTH-rP increase renal tubular calcium reabsorption in vivo (9), and Leydig tumor cells are known to produce a PTH-rP (35). A different mechanism for increasing renal tubular calcium reabsorption has been proposed by Bijvoet and his colleagues (36).…”

Parathyroid Hormone‐related Protein in Hypercalcaemia of Malignancy

“…All of this was strong evidence that HHM cancers produced a substance chemically distinct from PTH, but which acts upon PTH target cells through or in close association with the PTH receptor. Production of such activity was also shown to occur in certain animal tumours associated with humoral hypercalcaemia (Rodan et al, 1983;Rosol et al, 1987), in cell cultures established from these tumours, and in a cell culture established from a renal cortical carcinoma removed originally from a hypercalcaemic patient (Strewler et a1,,1983). …”

“…By this time appropriately sensitive and high-capacity biological assays for PTH had been developed, and an energetic search for PTH-like activity in tumours resulted in the demonstration that extracts of tumours from HHM patients contained no immunoassayable PTH but were able to activate adenylate cyclase in kidney membranes and increase cyclic AMP production in osteoblast-like cells Rodan et al, 1983). This adenylate cyclase-stimulating activity could be shown only in PTH target tissues, and was inhibited by peptide antagonists of PTH.…”

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.

“…Both PTH-like activity and TGF activity, especially of alpha class, have attracted much attention as a cause of HHM (Mundy et al, 1985;Rodan et al, 1983;Tashjian et al, 1986), but the simultaneous production of both activities by a particular HHM tumor has rarely been reported. Rat Leydig cell is the representative animal model of HHM and known to produce both PTH-like and TGF-alpha activities (Rodan et al, 1983;Ibbotson el al., 1983).…”

“…Rat Leydig cell is the representative animal model of HHM and known to produce both PTH-like and TGF-alpha activities (Rodan et al, 1983;Ibbotson el al., 1983). Employing CAC-8, a serially transplantable tumor line developed from a canine hypercalcemic adenocarcinoma, Rosol et al (1986) reported the simultaneous occurrence of PTH-like activity and EGF-independent TGF activity.…”