Human pituitary tumor-transforming gene induces angiogenesis

Angiogenesis is a key determinant and rate-limiting step in tumor progressi on and metastatic spread, As pituitary tumor-transforming gene (PTTG) induc es basic fibroblast growth factor (bFGF), we tested angiogenesis induced by conditioned medium (CM) derived from NIH-3T3 transfectants overexpressing wild-type human PTTG (WT-hPTTG-CM). We also examined the relationship betwe en PTTG expression and tumor vascularity in a series of human tumors. CM fr om Wt-hPTTG transfectants induced proliferation, migration, and tube format ion of human umbilical vein endothelial, cells in vitro. The bFGF concentra tion in WT-hPTTG-CM was elevated (10.5 +/- 0.56) compared with CM from nont ransfected NIH-3T3 cells (3.3 +/- 0.56 pg/mL), and addition of anti-bFGF an tibody to CM abrogated these angiogenesis markers (P < 0.01). In vivo, conc entrated WT-hPTTG-CM induced chick chorioallantoic membrane spoke-wheel-lik e appearances. Moreover, CM derived from hPTTG transfectants harboring a po int mutation on the C-terminus proline-rich region of PTTG induced weaker a ngiogenic activity than WT-hPTTG-CM (P < 0.01). Thus, human PTTG induces an angiogenic phenotype in both in vitro and in vivo angiogenesis models, and high PTTG messenger ribonucleic acid is associated with an angiogenic phen otype in human tumors. These PTTG-directed angiogenic actions may be mediat ed through bFGF, which also contributes to tumor growth.