Adenovirus-mediated interferon-beta gene transfer inhibits angiogenesis in and progression of orthotopic tumors of human prostate cancer cells in nude mice.
Interferon (IFN)-beta is a multifunctional cytokine. Our previous studies revealed that intratumoral transfer of the murine interferon (IFN)-beta gene inhibited the growth of human and mouse prostate cancer cells in mice. Since IFN-beta activity is species-restricted, we investigated the efficacy and mechanisms of forced expression of human IFN-beta in suppressing the growth of human prostate cancer cells in mice. Orthotopic tumors of PC-3MM2 human prostate cancer cells were forced to express human IFN-beta by intratumoral injection of an adenoviral vector (AdhIFN-beta). Tumor growth and survival of tumor-bearing mice were determined. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Angiogenesis and angiogenic molecule expression were evaluated by IHC and quantitative real-time reverse-transcriptional PCR (qRT-PCR). We found that forced expression of human IFN-beta inhibited tumor growth in a dose-dependent manner. An injection of 2 x 10(9) PFU (plaque-forming units) of AdhIFN-beta retarded tumor growth by 90% and prolonged the survival of tumor-bearing mice. Control tumors contained more proliferating cells (PCNA(+)) and fewer apoptotic cells (TUNEL(+)) than did AdhIFN-beta treated-tumors. Treatment with AdhIFN-beta downregulated the expression of interleukin-8 and vascular endothelial cell growth factor-A. Taken together, our data indicated that forced expression of human IFN-beta in human prostate cancer cells significantly inhibited their prostatic growth, which correlated with downregulation of angiogenic molecules and suggested that adenoviral vector-mediated IFN-beta gene therapy could be an effective approach for the management of human prostate cancer.
Lee
Juwon
J
Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Wang
Amy
A
Hu
Qiande
Q
Lu
Shan
S
Dong
Zhongyun
Z
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D015536:Down-Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D016209:Interleukin-8; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016899:Interferon-beta