TY - JOUR
T1 - Inhibition of tumorigenicity and metastasis of human bladder cancer growing in athymic mice by Interferon-β gene therapy results partially from various antiangiogenic effects including endothelial cell apoptosis
AU - Izawa, Jonathan I.
AU - Sweeney, Paul
AU - Perrotte, Paul
AU - Kedar, Daniel
AU - Dong, Zhongyun
AU - Slaton, Joel W.
AU - Karashima, Takashi
AU - Inoue, Keji
AU - Benedict, William F.
AU - Dinney, Colin P.N.
PY - 2002/4/1
Y1 - 2002/4/1
N2 - We determined whether the IFN-β gene could suppress angiogenesis, tumor growth, and metastasis of human bladder transitional cell carcinoma. The highly tumorigenic and metastatic 253J B-VR human bladder transitional cell carcinoma (TCC) cell line (resistant to the antiproliferative effects of IFN-β) was infected in vitro with adenoviral β-galactosidase (Ad-LacZ), murine adenoviral IFN-β (Ad-mIFN-β), or human adenoviral IFN-β (Ad-hIFN-β) and implanted into the bladders of athymic nude mice. Ad-mIFN-β and Ad-hIFN-β were used because of the species specificity of IFN-β. The transient production of mIFN-β and hIFN-β from the infected 253JB-VR tumor cells significantly inhibited tumorigenicity and spontaneous lymph node metastasis. Subsequently, the 253J B-VR cells were implanted into the subcutis of athymic nude mice, and established tumors were treated by direct intratumoral injection with AdmIFN-β, Ad-hIFN-β, Ad-LacZ, or PBS. By in situ hybridization (ISH) and immunohistochemical analysis (IHC), expression of hIFN-β and mIFN-β mRNA and protein within the tumors was demonstrated after Ad-hIFN-β and Ad-mIFN-β gene therapy, respectively. The therapy also induced necrosis in both the Ad-mIFN-β- and Ad-hIFN-β-treated tumors. IHC revealed decreased tumor cell proliferation and the sequestration of activated macrophages within the tumors after Ad-mIFN-β therapy. In addition, the expression of the proangiogenic factors bFGF, and MMP-9 protein (by IHC) was significantly down-regulated by Ad-hIFN-β 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-β gene therapy. Tumor-induced angiogenesis, as determined by the microvessel density, was decreased in tumors treated with both Ad-mIFN-β and Ad-hIFN-β. These data suggest that the inhibition of tumorigenicity and the metastasis of the 253J B-VR cells after infection with Ad-IFN-β is caused by the inhibition of angiogenesis and the activation of host effector cells.
AB - We determined whether the IFN-β gene could suppress angiogenesis, tumor growth, and metastasis of human bladder transitional cell carcinoma. The highly tumorigenic and metastatic 253J B-VR human bladder transitional cell carcinoma (TCC) cell line (resistant to the antiproliferative effects of IFN-β) was infected in vitro with adenoviral β-galactosidase (Ad-LacZ), murine adenoviral IFN-β (Ad-mIFN-β), or human adenoviral IFN-β (Ad-hIFN-β) and implanted into the bladders of athymic nude mice. Ad-mIFN-β and Ad-hIFN-β were used because of the species specificity of IFN-β. The transient production of mIFN-β and hIFN-β from the infected 253JB-VR tumor cells significantly inhibited tumorigenicity and spontaneous lymph node metastasis. Subsequently, the 253J B-VR cells were implanted into the subcutis of athymic nude mice, and established tumors were treated by direct intratumoral injection with AdmIFN-β, Ad-hIFN-β, Ad-LacZ, or PBS. By in situ hybridization (ISH) and immunohistochemical analysis (IHC), expression of hIFN-β and mIFN-β mRNA and protein within the tumors was demonstrated after Ad-hIFN-β and Ad-mIFN-β gene therapy, respectively. The therapy also induced necrosis in both the Ad-mIFN-β- and Ad-hIFN-β-treated tumors. IHC revealed decreased tumor cell proliferation and the sequestration of activated macrophages within the tumors after Ad-mIFN-β therapy. In addition, the expression of the proangiogenic factors bFGF, and MMP-9 protein (by IHC) was significantly down-regulated by Ad-hIFN-β 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-β gene therapy. Tumor-induced angiogenesis, as determined by the microvessel density, was decreased in tumors treated with both Ad-mIFN-β and Ad-hIFN-β. These data suggest that the inhibition of tumorigenicity and the metastasis of the 253J B-VR cells after infection with Ad-IFN-β is caused by the inhibition of angiogenesis and the activation of host effector cells.
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M3 - Article
C2 - 11948141
AN - SCOPUS:0036554710
SN - 1078-0432
VL - 8
SP - 1258
EP - 1270
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -