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 endothelial cells both in vitro and in vivo. Results of in vivo diffusion chamber assay showed a clear hypervascularization on the outer surface of diffusion chambers containing mGH3 tumor cell implants but not in those containing GH3 cells. Co-incubation with antisense PTHrP oligonucleotide (10 microM), but not sense or mismatched PTHrP oligonucleotide, suppressed hypervascularization in diffusion chambers. To further examine the role of PTHrP on endothelial cell function, PTHrP(1-34) was added at various concentrations to cultured 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 similar increase in tube formation, which was dose-dependently inhibited by H89, a protein kinase A inhibitor. Our results indicate for the first time that PTHrP is a potential paracrine factor acting via the PKA pathway to enhance angiogenesis through capillary tube formation by endothelial cells in malignant pituitary tumors.
Akino
K
K
Department of Anatomy, Nagasaki University School of Medicine, Japan.
Ohtsuru
A
A
Kanda
K
K
Yasuda
A
A
Yamamoto
T
T
Akino
Y
Y
Naito
S
S
Kurokawa
M
M
Iwahori
N
N
Yamashita
S
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013006:Growth Hormone / Q000032:analysis; D007546:Isoquinolines / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D016376:Oligonucleotides, Antisense; D044162:Parathyroid Hormone-Related Protein; D010902:Pituitary Gland; D010911:Pituitary Neoplasms / Q000098:blood supply*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D016376:Oligonucleotides, Antisense; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013006:Growth Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide