Adenovirus-mediated interferon-beta gene transfer inhibits angiogenesis in and progression of orthotopic tumors of human prostate cancer cells in nude mice

Abstract

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.