Over-production of parathyroid hormone-related peptide results in increased osteolytic skeletal metastasis by prostate cancer cells in vivo.

Prostate carcinoma is one of the most common malignancies affecting males, resulting in a high rate of morbidity and mortality. This hormone-dependent malignancy is characteristically associated with a high incidence of osteoblastic skeletal lesions. However, osteolytic lesions invariably accompany blastic ones. In the current study, we assessed the role of parathyroid hormone-related peptide (PTHRP), a potent bone-resorbing agent, in contributing to bone breakdown and prostatic skeletal metastasis using a syngeneic rat prostate cancer model. The full-length cDNA encoding rat PTHRP was subcloned as a Hind III insert in the sense orientation into the mammalian expression vector pRc-CMV to generate the expression vector pRc-PTHRP-S. Both control and experimental plasmids were stably transfected into low PTHRP-producing Dunning R3227, Mat Ly Lu rat prostate cancer cells. Following antibiotic selection, monoclonal cell lines expressing the highest amount of PTHRP mRNA and immunoreactive PTHRP were selected as experimental tumor cells for further analysis. Increased PTHRP production by these cells had no significant effect in vitro on the invasive capacity of these cells. Control and experimental cells were inoculated s.c. into the right flank or by the intracardiac (i.c.) route into the left ventricle of inbred male Copenhagen rats. No skeletal metastases occurred after s.c. injection with either cells. In contrast, i.c. inoculation led to lumbar vertebra metastasis and consequent hind-limb paralysis. Furthermore, histological examination of skeletal metastases in experimental animals showed a marked increase in osteoclastic activity. Our results demonstrate that PTHRP can increase osteoclastic osteolysis in the presence of focal osseous prostate cancer metastases and may contribute to the lytic lesions which generally accompany osteoblastic lesions in prostate cancer.