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Inhibition of Tumorigenicity and Metastasis of Human Bladder Cancer Growing in Athymic Mice by Interferon-ß Gene Therapy Results Partially from Various Antiangiogenic Effects Including Endothelial Cell Apoptosis¹

Departments of Cancer Biology [J. I. I., P. S., P. P., D. K., Z. D., J. W. S., T. K., C. P. N. D.], Urology [J. I. I., D. K., J. W. S., C. P. N. D.], and Genitourinary Medical Oncology [W. F. B.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Department of Urology, Kochi Medical School, Kochi, Japan [K. I.]

We determined whether the IFN-ß gene could suppress angiogenesis, tumor growth, and metastasis of human bladder transitional cell carcinoma. The highly tumorigenic and metastatic 253J B-V^R human bladder transitional cell carcinoma (TCC) cell line (resistant to the antiproliferative effects of IFN-ß) was infected in vitro with adenoviral ß-galactosidase (Ad-LacZ), murine adenoviral IFN-ß (Ad-mIFN-ß), or human adenoviral IFN-ß (Ad-hIFN-ß) and implanted into the bladders of athymic nude mice. Ad-mIFN-ß and Ad-hIFN-ß were used because of the species specificity of IFN-ß. The transient production of mIFN-ß and hIFN-ß from the infected 253JB-V^R tumor cells significantly inhibited tumorigenicity and spontaneous lymph node metastasis. Subsequently, the 253J B-V^R cells were implanted into the subcutis of athymic nude mice, and established tumors were treated by direct intratumoral injection with Ad-mIFN-ß, Ad-hIFN-ß, Ad-LacZ, or PBS. By in situ hybridization (ISH) and immunohistochemical analysis (IHC), expression of hIFN-ß and mIFN-ß mRNA and protein within the tumors was demonstrated after Ad-hIFN-ß and Ad-mIFN-ß gene therapy, respectively. The therapy also induced necrosis in both the Ad-mIFN-ß- and Ad-hIFN-ß-treated tumors. IHC revealed decreased tumor cell proliferation and the sequestration of activated macrophages within the tumors after Ad-mIFN-ß therapy. In addition, the expression of the proangiogenic factors bFGF, and MMP-9 protein (by IHC) was significantly down-regulated by Ad-hIFN-ß gene therapy. Double-immunofluorescent IHC for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and CD-31 demonstrated tumor and endothelial cell apoptosis in those tumors treated with Ad-hIFN-ß gene therapy. Tumor-induced angiogenesis, as determined by the microvessel density, was decreased in tumors treated with both Ad-mIFN-ß and Ad-hIFN-ß. These data suggest that the inhibition of tumorigenicity and the metastasis of the 253J B-V^R cells after infection with Ad-IFN-ß is caused by the inhibition of angiogenesis and the activation of host effector cells.

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