Human Pituitary Tumor-Transforming Gene Induces Angiogenesis¹

Abstract

Angiogenesis is a key determinant and rate-limiting step in tumor progression and metastatic spread. As pituitary tumor-transforming gene (PTTG) induces 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 between PTTG expression and tumor vascularity in a series of human tumors. CM from Wt-hPTTG transfectants induced proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. The bFGF concentration in WT-hPTTG-CM was elevated (10.5 +/- 0.56) compared with CM from nontransfected NIH-3T3 cells (3.3 +/- 0.56 pg/mL), and addition of anti-bFGF antibody to CM abrogated these angiogenesis markers (P < 0.01). In vivo, concentrated WT-hPTTG-CM induced chick chorioallantoic membrane spoke-wheel-like appearances. Moreover, CM derived from hPTTG transfectants harboring a point mutation on the C-terminus proline-rich region of PTTG induced weaker angiogenic 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 phenotype in human tumors. These PTTG-directed angiogenic actions may be mediated through bFGF, which also contributes to tumor growth.