Bcl-2 mediated modulation of vascularization in prostate cancer xenografts.
OBJECTIVE
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.


METHODS
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.
Sakai
Yoshihisa
Y
Department of Urology, University of Florida College of Medicine, Gainesville, Florida 32601, USA.
Goodison
Steve
S
Kusmartsev
Sergei
S
Fletcher
Bradley
B
Eruslanov
Evgeniy
E
Cao
Wengang
W
Porvasnik
Stacy
S
Namiki
Kazunori
K
Anai
Satoshi
S
Rosser
Charles J
CJ
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016209:Interleukin-8; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020780:Matrix Metalloproteinase 9