Parathyroid hormone-related peptide is a potent tumor angiogenic factor

Rat pituitary malignant tumor cells; mGH3, show hypervascularization in in vivo xenografts and overexpress parathyroid hormone-related peptide (PTHrP) compared to original GH3 cells. To elucidate whether PTHrP is involved in tumor-derived angiogenesis, we examined the effect of PTHrP on vascular end othelial cells both in vitro and in vivo. Results of in vivo diffusion cham ber assay showed a clear hypervascularization on the outer surface of diffu sion chambers containing mGH3 tumor cell implants but not in those containi ng GH3 cells. Go-incubation with antisense PTHrP oligonucleotide (10 muM), but not sense or mismatched PTHrP oligonucleotide, suppressed hypervascular ization in diffusion chambers. To further examine the role of PTHrP on endo thelial cell function, PTHrP(1-34) was added at various concentrations to c ultured bovine endothelial cells (BAECs) harvested from the aorta. PTHrP(1- 34) did not alter the proliferation or migration of endothelial cells, but rather dose-dependently increased capillary formation by endothelial cells on the collagen gel matrix. Furthermore, 0.1 mM of 8-bromo-cAMP caused a si milar increase in tube formation, which was dose-dependently inhibited by H 89, a protein kinase A inhibitor. Our results indicate for the first time t hat PTHrP is a potential paracrine factor acting via the PKA pathway to enh ance angiogenesis through capillary tube formation by endothelial cells in malignant pituitary tumors.