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 (TGFbeta) 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 TGFbeta 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 TGFbeta-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 TGFbeta blockade by systemic sBG administration can inhibit DU145 prostate xenograft growth and angiogenesis. The inhibition is likely in part mediated by the attenuation of TGFbeta-induced MMP-9 expression.
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Abhik
A
Bandyopadhyay
Long
L
Wang
Fernando
F
López-Casillas
Valentín
V
Mendoza
I-Tien
IT
Yeh
LuZhe
L
Sun
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011509:Proteoglycans / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C071736:betaglycan; D020780:Matrix Metalloproteinase 9