BACKGROUND: Parathyroid hormone-related protein (PTH-rP) has been implicated as a causative factor in the humoral hypercalcemia of malignancy. Animal models of hypercalcemia of malignancy that have traditionally utilized human or animal tumors or injections or infusions of hypercalcemic factors have limitations that may prevent exact delineation of the biologic effects of tumor-produced PTH-rP. EXPERIMENTAL DESIGN: To assess the effects of tumor-produced PTH-rP in vivo, we have transfected Chinese hamster ovarian (CHO) cells with cDNA encoding human preproPTH-rP-(1-141) which then stably express only PTH-rP. We inoculated these tumor cells into nude mice, and compared tumor-bearing nude mice with similar tumor-bearing nude mice inoculated with non-transfected CHO cells using standard parameters of calcium homeostasis. RESULTS: The nude mice carrying tumors expressing PTH-rP became hypercalcemic over 12 to 18 days. Blood ionized calcium values correlated positively with plasma PTH-rP concentration and tumor volume. Plasma PTH-rP concentrations in hypercalcemic mice were similar to those reported in humans with hypercalcemia of malignancy. Bone histology and histomorphometry from hypercalcemic nude mice demonstrated increased bone resorption when compared with mice bearing nontransfected CHO tumors. CONCLUSIONS: We have produced an animal model of tumor-produced PTH-rP by transfecting CHO cells with the cDNA for PTH-rP and inoculating these tumor cells into nude mice. Hypercalcemia in this model is mediated in part by the effects of PTH-rP to increase osteoclastic bone resorption. The model is advantageous because PTH-rP alone is secreted in a prolonged, constitutive fashion with pharmacokinetics similar to naturally occurring tumors. It should prove to be a useful model to study the effects of tumor-produced PTH-rP in vivo.
BACKGROUND:Parathyroid hormone-related protein (PTH-rP) has been implicated as a causative factor in the humoral hypercalcemia of malignancy. Animal models of hypercalcemia of malignancy that have traditionally utilized human or animal tumors or injections or infusions of hypercalcemic factors have limitations that may prevent exact delineation of the biologic effects of tumor-produced PTH-rP. EXPERIMENTAL DESIGN: To assess the effects of tumor-produced PTH-rP in vivo, we have transfected Chinese hamster ovarian (CHO) cells with cDNA encoding human preproPTH-rP-(1-141) which then stably express only PTH-rP. We inoculated these tumor cells into nude mice, and compared tumor-bearing nude mice with similar tumor-bearing nude mice inoculated with non-transfected CHO cells using standard parameters of calcium homeostasis. RESULTS: The nude mice carrying tumors expressing PTH-rP became hypercalcemic over 12 to 18 days. Blood ionizedcalcium values correlated positively with plasma PTH-rP concentration and tumor volume. Plasma PTH-rP concentrations in hypercalcemic mice were similar to those reported in humans with hypercalcemia of malignancy. Bone histology and histomorphometry from hypercalcemic nude mice demonstrated increased bone resorption when compared with mice bearing nontransfected CHO tumors. CONCLUSIONS: We have produced an animal model of tumor-produced PTH-rP by transfecting CHO cells with the cDNA for PTH-rP and inoculating these tumor cells into nude mice. Hypercalcemia in this model is mediated in part by the effects of PTH-rP to increase osteoclastic bone resorption. The model is advantageous because PTH-rP alone is secreted in a prolonged, constitutive fashion with pharmacokinetics similar to naturally occurring tumors. It should prove to be a useful model to study the effects of tumor-produced PTH-rP in vivo.
Authors: J J Yin; K Selander; J M Chirgwin; M Dallas; B G Grubbs; R Wieser; J Massagué; G R Mundy; T A Guise Journal: J Clin Invest Date: 1999-01 Impact factor: 14.808