Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft.
We have demonstrated previously that ectopic expression of a soluble betaglycan, also known as transforming growth factor (TGF) beta type III receptor, can suppress the malignant properties of human carcinoma cells by antagonizing the tumor-promoting activity of TGF-beta (A. Bandyopadhyay et al., Cancer Res., 59: 5041-5046, 1999). In the current study, we investigated the potential therapeutic utility of a recombinant preparation of human and rat soluble betaglycan (sBG). Purified recombinant human sBG showed similar properties to its rat counterpart (M. M. Vilchis-Landeros et al., Biochem J., 355: 215-222, 2001). It bound TGF-beta with high affinity and isoform selectivity and neutralized the activity of TGF-beta(1) in two bioassays. Peritumoral (50 micro g/tumor, twice a week) or i.p. (100 micro g/animal, every alternate day) injection of sBG into human breast carcinoma MDA-MB-231 xenograft-bearing athymic nude mice significantly inhibited the tumor growth. The administration of sBG also reduced metastatic incidence and colonies in the lungs. The tumor-inhibitory activity of sBG was found to be associated with the inhibition of angiogenesis. Systemic sBG treatment significantly reduced tumor microvessel density detected with histological analyses and CD-31 immunostainings, as well as tumor blood volume measured with hemoglobin content. In an in vitro angiogenesis assay, treatment with the recombinant sBG significantly reduced the ability of human dermal microvascular endothelial cells to form a capillary tube-like structure on Matrigel. These findings support the conclusion that sBG treatment suppresses tumor growth and metastasis, at least in part by inhibiting angiogenesis. As such, it could be a useful therapeutic agent to antagonize the tumor-promoting activity of TGF-beta.
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
Abhik
A
Bandyopadhyay
Fernando
F
López-Casillas
Shazli N
SN
Malik
José Luis
JL
Montiel
Valentín
V
Mendoza
Junhua
J
Yang
L-Z
LZ
Sun
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008907:Mink; D011509:Proteoglycans / Q000494:pharmacology*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C071736:betaglycan