Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer

BACKGROUND. Transforming growth factor beta (TGFβ) over-expression in prostate cancer has been shown to promote tumor progression and neo-vascularization. In this study, we have investigated the efficacy and the potential mechanism of a TGFβ antagonist, a recombinant soluble betaglycan (sBG), as a prostate cancer therapeutic agent after systemic administration in a xenograft model. METHODS. Recombinant sBG was delivered continuously via ALZET osmotic pumps or by daily bolus i.p. injection at 4.2 mg/kg/day for 14 days in human prostate cancer DU145 xenograft bearing nude mice. Tumors were analyzed for their size, blood volume by hemoglobin assay, microvessel density (MVD) by CD-31 immunostaining, and apoptosis by TUNEL assay. Matrix metalloproteinase-9 (MMP-9) activity and expression in the DU145 conditioned media were determined by gelatin zymography and Western blotting, respectively. Tissue sections were stained with a polyclonal antibody to MMP-9 using an immuno-fluorescence method. RESULTS. Continuous or bolus administration of sBG showed a similar significant inhibition of DU145 xenograft growth associated with a reduced tumor blood volume and MVD, and an enhanced intra-tumoral apoptosis. Treatment with sBG inhibited both endogenous and TGFβ-induced MMP-9 activity and expression, in a dose-dependent manner in vitro and reduced in vivo MMP-9 expression in DU145 xenografts. CONCLUSIONS. Our results for the first time indicate that TGFβ blockade by systemic sBG administration can inhibit DU145 prostate xenograft growth and angiogenesis. The inhibition is likely in part mediated by the attenuation of TGFβ-induced MMP-9 expression.