Inhibition of ascites tumor growth in vivo by sTie-2 is potentiated by a combinatorial therapy with sFLT-1

• Published in: The journal of gene medicine 2010-12, Vol.12 (12), p.968-980
• Main Authors: D'Souza, Saritha Sandra, Gururaj, Anupama E., Raj, Harsha M., Rössler, Jochen, Salimath, Bharathi P.
• Format: Article
• Language: English
• Subjects: angiogenesis; Angiopoietin-2; angiopoietins; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ascites; Baculovirus; Carcinoma, Ehrlich Tumor - metabolism; Carcinoma, Ehrlich Tumor - pathology; Carcinoma, Ehrlich Tumor - therapy; Cell Proliferation - drug effects; Gene therapy; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - prevention & control; Receptor, TIE-2 - genetics; Receptor, TIE-2 - therapeutic use; recombinant sTie-2; sFLT-1; Solubility; Transfection - methods; Transplants; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-1 - therapeutic use
• ISSN: 1099-498X; 1521-2254; 1521-2254
• DOI: 10.1002/jgm.1520

Background Inhibition of tumor angiogenesis is a promising approach for cancer therapy and the Tie‐2/angiopoietin pathway appears to play an important role. In the present study, we have developed strategies to explore the therapeutic potential of blocking the Tie‐2/angiopoietin pathway by sTie‐2. Methods Ehrlich ascites tumor (EAT) cells were stably transfected to overexpress a truncated form of sTie‐2. Transfectants were characterized for their in vitro growth behavior and transplanted into nude mice. Furthermore, recombinant sTie‐2 produced by the baculovirus expression system was used to sequester angiopoietins in the murine ascites carcinoma model. The effect of sTie‐2 treatment alone or in combination with sFLT‐1 on the weight of the animal, ascites cell number and volume was studied. Results EAT cells stably transfected with a truncated form of sTie‐2 showed no change in cell proliferation in vitro and colony forming in soft agar compared to control cells. However, sTie‐2 transfected EAT cells transplanted into nude mice reduced tumor burden and demonstrated a reduction in ascites formation and peritoneal angiogenesis. Recombinant sTie‐2 showed angiogenic activity in the tube formation and wound healing assay in vitro. sTie‐2 treatment alone or in combination with sFLT‐1 in an ascites tumor mouse model resulted in reduced peritoneal angiogenesis, with a concomitant decrease in tumor cell number, volume of ascites and the number of invasive tumor cells, as assayed by CD31 staining. Conclusions The findings of the present study demonstrate an important role for the Tie‐2/angiopoietin pathway in the formation of tumor vasculature and suggest that sTie‐2 might yield useful anticancer therapy. Copyright © 2010 John Wiley & Sons, Ltd.