Current Gene Therapy

Ignacio Anegon
Director INSERM UMR 1064-Center for Research in Transplantation and Immunology
CHU de Nantes. 30, boulevard
Nantes
France

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Endoglin Silencing has Significant Antitumor Effect on Murine Mammary Adenocarcinoma Mediated by Vascular Targeted Effect

Author(s): Tanja Dolinsek, Bostjan Markelc, Masa Bosnjak, Tanja Blagus, Lara Prosen, Simona Kranjc, Monika Stimac, Ursa Lampreht, Gregor Sersa, Maja Cemazar.

Abstract:

New targets and therapeutic approaches for vascular targeted strategies in oncology are continuously explored. Endoglin, a co-receptor of TGF-β, is a known target, however, its silencing with vector-based RNA interference technology has not been evaluated yet. Therefore, in our study, we assembled plasmid DNA coding for shRNA against endoglin, and used gene electrotransfer as a delivery method to determine its antitumor and vascular targeted effects. In vitro and in vivo data provide evidence of vascular targeted effects of endoglin silencing. The vascular targeted action of endoglin silencing could be described as a result of two separated effect; antiangiogenic and vascular disrupting effect. This was first supported by in vitro data; predominantly by reduction of proliferation and tube formation of endothelial cells. In the TS/A murine mammary carcinoma model, in which the tumor cells do not express endoglin, reduced tumor growth and number of vessels were observed. Quick destruction of existing activated blood vessels at the site of tumor cells’ injection and sustained growth of tumors afterwards was observed in tumors that were growing in dorsal window chamber by intravital microscopy. This observation supports both vascular disrupting and antiangiogenic action. In conclusion, the results of our study provide evidence of endoglin as a valid target for cancer therapy and support further development of plasmid shRNA delivery, which have prolonged antitumor effect, especially in combined schedules.

Keywords: Endoglin, DNA, Adenocarcinoma, shRNA.

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Article Details

VOLUME: 15
ISSUE: 3
Year: 2015
Page: [228 - 244]
Pages: 17
DOI: 10.2174/1566523215666150126115501
Price: $58