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Bcl‐2 mediated modulation of vascularization in prostate cancer xenografts
Author(s) -
Sakai Yoshihisa,
Goodison Steve,
Kusmartsev Sergei,
Fletcher Bradley,
Eruslanov Evgeniy,
Cao Wengang,
Porvasnik Stacy,
Namiki Kazunori,
Anai Satoshi,
Rosser Charles J.
Publication year - 2008
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20888
Subject(s) - angiogenesis , lymphangiogenesis , cancer research , prostate cancer , basic fibroblast growth factor , neovascularization , biology , vascular endothelial growth factor , medicine , cancer , metastasis , growth factor , receptor , vegf receptors
PURPOSE We previously demonstrated that Bcl‐2 overexpression enhances the radiation resistance of PC‐3 human prostate cancer cells and xenografts by inhibiting apoptosis, increasing proliferation, and promoting angiogenesis. To further elucidate the relationship between Bcl‐2 expression and the angiogenic potential of PC‐3‐Bcl‐2 cells, tumorigenicity, angiogenesis, and lymphangiogenesis were evaluated and compared in a Bcl‐2 overexpressing clone in vitro and in vivo. EXPERIMENTAL DESIGN Human prostate cancer cells over expressing Bcl‐2 were studied in vitro and in vivo to determine the angiogenic and lymphangiogenic properties of these cells. RESULTS Increased Bcl‐2 expression enhanced the tumorigenicity of prostate cancer xenografts. It also enhanced the expression and secretion of key angiogenic and lymphangiogenic factors that stimulated the synthesis of CD31‐positive blood vessels and LYVE‐1 positive lymphatics. Specifically, the increased angiogenic and lymphangiogenic potential correlated with increased serum levels of basic fibroblast growth factor (bFGF), interleukin 8 (CXCL8), and matrix metalloproteinase (MMP 9). In vitro analysis demonstrated that Bcl‐2 expressing tumor cells secreted bFGF and vascular endothelial growth factor (VEGF) into culture supernatants. Microarray analysis of Bcl‐2 expressing PC‐3 cells demonstrated increased transcription of genes involved in metabolism, such as interleukins, growth factors, tumor necrosis factors (TNF) family members, and peptidases. CONCLUSIONS Together, these results demonstrate that Bcl‐2 can regulate tumoral angiogenesis and lymphangiogenesis and suggest that therapy targeted at Bcl‐2 expression, angiogenesis, and lymphangiogenesis may synergistically modulate tumor growth and confirm that Bcl‐2 is a pivotal target for cancer therapy. Prostate 69:459–470, 2009. © 2008 Wiley‐Liss, Inc.