51. Tumor-infiltrating macrophages are involved in suppressing growth and metastasis of human prostate cancer cells by INF-beta gene therapy in nude mice
- Author
-
Fahao, Zhang, Weixin, Lu, and Zhongyun, Dong
- Subjects
Male ,Genetic Vectors ,Mice, Nude ,Nitric Oxide Synthase Type II ,Injections, Intralesional ,Adenoviridae ,Transforming Growth Factor beta1 ,Mice ,Transforming Growth Factor beta ,Tumor Cells, Cultured ,Animals ,Humans ,Immunologic Factors ,Neoplasm Metastasis ,Mice, Inbred BALB C ,Macrophages ,Interleukin-8 ,Prostatic Neoplasms ,Genetic Therapy ,Interferon-beta ,Xenograft Model Antitumor Assays ,Neoplasm Proteins ,Specific Pathogen-Free Organisms ,Gene Expression Regulation, Neoplastic ,Nitric Oxide Synthase ,Cell Division - Abstract
This study was to determine the role of tumor-infiltrating macrophages in IFN-beta-induced host defense against prostate cancer.Efficacy of adenovirus-mediated IFN-beta gene therapy against orthotopic xenografts of human prostate cancer was tested in macrophage-compromised nude mice. Immunohistochemistry and Northern blotting were used to elucidate mechanisms responsible for the IFN-beta gene therapy.PC-3MM2 human prostate cancer cells were inoculated into the prostates of nude mice. Intralesional injection of an adenoviral vector-encoding murine IFN-beta (AdmIFN-beta) but not control vector AdE/1 suppressed growth of PC-3MM2 tumors in a dose-dependent manner, with a maximal reduction of tumor weight by approximately 85% at 2 x 10(9) plaque-forming units. The therapy prevented metastasis, eradicated established metastases in some mice, and prolonged the survival of tumor-bearing mice. The efficacy of AdmIFN-beta therapy was reduced significantly in mice treated with macrophage-selective anti-Mac-1 and anti-Mac-2 antibodies. Moreover, the i.p. injection of the antibodies restored the tumorigenicity of PC-3MM2 cells stably engineered with murine IFN-beta gene. Tumor-infiltrating macrophages, significantly increased in AdmIFN-beta-injected lesions, were depleted by the antibodies. The therapy stimulated expression of the inducible nitric oxide synthase, down-regulated transforming growth factor-beta1 and interleukin-8, reduced microvessel density, and resulted in apoptosis of endothelial cells in the lesions. These effects of AdmIFN-beta were partially diminished in mice treated with the antibodies.These data suggest that macrophages play an important role in IFN-beta gene therapy and that intralesional delivery of the IFN-beta gene could be an effective therapy for clinically localized human prostate cancer.
- Published
- 2002