Tumor-infiltrating macrophages are involved in suppressing growth and metastasis of human prostate cancer cells by INF-beta gene therapy in nude mice.
OBJECTIVE
This study was to determine the role of tumor-infiltrating macrophages in IFN-beta-induced host defense against prostate cancer.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Zhang
Fahao
F
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lu
Weixin
W
Dong
Zhongyun
Z
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D015552:Injections, Intralesional; D016899:Interferon-beta / Q000235:genetics / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D007155:Immunologic Factors; D016209:Interleukin-8; D009363:Neoplasm Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016899:Interferon-beta; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse