TheProstate69:459^470(2009) Bcl-2 Mediated Modulation of Vascularizationin Prostate Cancer Xenografts Yoshihisa Sakai, 1,2 Steve Goodison, 2,3 Sergei Kusmartsev, 1 Bradley Fletcher, 4 Evgeniy Eruslanov, 1 Wengang Cao, 1,2 Stacy Porvasnik, 1,2 Kazunori Namiki, 1,2 Satoshi Anai, 5 and Charles J. Rosser 1,2,4 * 1 Departmentof Urology,Gainesville,Florida 2 Prostate CancerTranslational Working Group,Universityof Florida,Gainesville,Florida 3 Departmentof Surgery-Jacksonville,Gainesville,Florida 4 Departmentof Pharmacologyand Therapeutics,Gainesville,Florida 5 Nara Medical University,Nara, Japan 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 lymphangio- genic 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. KEY WORDS: Bcl-2; microenvironment; vascular endothelial growth factor; basic fibroblast growth factor; angiogenesis; lymphangiogenesis Additional supporting information may be found in the online version of this article. Abbreviations: PSA, prostate specific antigen; VEGF, vascular endothelial growth factor; MVD, microvessel density; LVA, lymph vessel area; bFGF, basic fibroblast growth factor. Yoshihisa Sakai and Steve Goodison contributed equally to this work. Grant sponsor: Florida Department of Health James & Esther King Biomedical Grant. *Correspondence to: Charles J. Rosser, Department of Urology, University of Florida College of Medicine, Suite N215 P.O. Box 100247 Gainesville, FL 32601. E-mail: charles.rosser@urology.ufl.edu Received 6 August 2008; Accepted 9 October 2008 DOI 10.1002/pros.20888 Published online 23 December 2008 in Wiley InterScience (www.interscience.wiley.com). ß 2008 Wiley-Liss,Inc.