PURPOSE: We have previously demonstrated that prostate tumors that highly express Bcl-2 are not only more tumorigenic, but also more angiogenic than low Bcl-2 expressing tumors. Observed increased rates of angiogenesis are likely due to the secretion of multiple factors from the tumor cells. EXPERIMENTAL DESIGN: Human endothelial cells were subjected to exogenous VEGF or conditioned media from PC-3 cells and assayed by several in vitro systems to better characterize the effects of tumor microenvironment on endothelial cells. RESULTS: VEGF stimulation increased Bcl-2 expression in human microvascular endothelial cells (HMVECs), at least partially through stabilization of Bcl-2 mRNA transcripts, and protected these cells from apoptosis. These effects were mimicked by treatment of HMVECs with conditioned media from cultured PC-3 prostate tumor cells manipulated to overexpress Bcl-2. Through the use of kinase inhibitors and molecular profiling, several distinct pathways were implicated in the regulation of Bcl-2 in HMVECs, including those involving PI3K/AKT, PKC, mTOR, STAT-1, and IL-8, factors associated with tumor survival and growth. CONCLUSIONS: This study identifies molecular elements of a link between Bcl-2 expression in distinct cell types within a tumor and reaffirms that strategies designed to target Bcl-2 are desirable as they might enhance treatment response through dual effects.
PURPOSE: We have previously demonstrated that prostate tumors that highly express Bcl-2 are not only more tumorigenic, but also more angiogenic than low Bcl-2 expressing tumors. Observed increased rates of angiogenesis are likely due to the secretion of multiple factors from the tumor cells. EXPERIMENTAL DESIGN:Human endothelial cells were subjected to exogenous VEGF or conditioned media from PC-3 cells and assayed by several in vitro systems to better characterize the effects of tumor microenvironment on endothelial cells. RESULTS:VEGF stimulation increased Bcl-2 expression in human microvascular endothelial cells (HMVECs), at least partially through stabilization of Bcl-2 mRNA transcripts, and protected these cells from apoptosis. These effects were mimicked by treatment of HMVECs with conditioned media from cultured PC-3prostate tumor cells manipulated to overexpress Bcl-2. Through the use of kinase inhibitors and molecular profiling, several distinct pathways were implicated in the regulation of Bcl-2 in HMVECs, including those involving PI3K/AKT, PKC, mTOR, STAT-1, and IL-8, factors associated with tumor survival and growth. CONCLUSIONS: This study identifies molecular elements of a link between Bcl-2 expression in distinct cell types within a tumor and reaffirms that strategies designed to target Bcl-2 are desirable as they might enhance treatment response through dual effects.
Authors: Virginia Urquidi; Derek Sloan; Kanji Kawai; Dianne Agarwal; Anthony C Woodman; David Tarin; Steve Goodison Journal: Clin Cancer Res Date: 2002-01 Impact factor: 12.531
Authors: G Schumacher; E M Bruckheimer; A W Beham; T Honda; S Brisbay; J A Roth; C Logothetis; T J McDonnell Journal: Int J Cancer Date: 2001-01-15 Impact factor: 7.396
Authors: S Takemoto; J C Mulloy; A Cereseto; T S Migone; B K Patel; M Matsuoka; K Yamaguchi; K Takatsuki; S Kamihira; J D White; W J Leonard; T Waldmann; G Franchini Journal: Proc Natl Acad Sci U S A Date: 1997-12-09 Impact factor: 11.205
Authors: Scott M Wilhelm; Lila Adnane; Philippa Newell; Augusto Villanueva; Josep M Llovet; Mark Lynch Journal: Mol Cancer Ther Date: 2008-10 Impact factor: 6.261