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

Abstract

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.

• Authors: Yoshihisa Sakai, Steve Goodison, Sergei Kusmartsev, Bradley Fletcher, Evgeniy Eruslanov, Wengang Cao, Stacy Porvasnik, Kazunori Namiki, Satoshi Anai, Charles J Rosser
• Journal: The Prostate (Prostate) Vol. 69 Issue 5 Pg. 459-70 (Apr 01 2009) ISSN: 1097-0045 [Electronic] United States
• PMID: 19107861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Interleukin-8
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Fibroblast Growth Factor 2
• Matrix Metalloproteinase 9

Topics

• Adenocarcinoma (blood supply, metabolism, pathology)
• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Endothelium, Lymphatic (metabolism, pathology)
• Endothelium, Vascular (metabolism, pathology)
• Fibroblast Growth Factor 2 (metabolism)
• Humans
• Interleukin-8 (metabolism)
• Lymphangiogenesis (physiology)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microvessels (metabolism, pathology)
• Neovascularization, Pathologic (metabolism)
• Prostatic Neoplasms (blood supply, metabolism, pathology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Messenger (metabolism)
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor A (metabolism)