Tumor radiosensitization by gene electrotransfer-mediated double targeting of tumor vasculature

Savarin, Monika (author), Žnidar, Katarina (author), Serša, Gregor (author), Komel, Tilen (author), Čemažar, Maja (author), Kamenšek, Urška (author)

Targeting the tumor vasculature through specific endothelial cell markers involved in different signaling pathways represents a promising tool for tumor radiosensitization. Two prominent targets are endoglin (CD105), a transforming growth factor β co-receptor, and the melanoma cell adhesion molecule (CD1046), present also on many tumors. In our recent in vitro study, we constructed and evaluated a plasmid for simultaneous silencing of these two targets. In the current study, our aim was to explore the therapeutic potential of gene electrotransfer-mediated delivery of this new plasmid in vivo, and to elucidate the effects of combined therapy with tumor irradiation. The antitumor effect was evaluated by determination of tumor growth delay and proportion of tumor free mice in the syngeneic murine mammary adenocarcinoma tumor model TS/A. Histological analysis of tumors (vascularization, proliferation, hypoxia, necrosis, apoptosis and infiltration of immune cells) was performed to evaluate the therapeutic mechanisms. Additionally, potential activation of the immune response was evaluated by determining the induction of DNA sensor STING and selected pro-inflammatory cytokines using qRT-PCR. The results point to a significant radiosensitization and a good therapeutic potential of this gene therapy approach in an otherwise radioresistant and immunologically cold TS/A tumor model, making it a promising novel treatment modality for a wide range of tumors.

• Language: English
• Keywords: gene electrotransfer, adenocarcinom, radiosensitization, silencing plasmid, antivascular shRNA, CD105, CD1046, DNA sensors, murine mammary adenocarcinoma TS/A
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: ZF - Faculty of Health Sciences; MF - Faculty of Medicine; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 14 str.
• Numbering: Vol. 24, iss. 3, art. 2755
• PID: 20.500.12556/RUL-155597
• UDC: 602
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms24032755
• COBISS.SI-ID: 140588547
• Publication date in RUL: 08.04.2024

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: genski elektroprenos, adenokarcinom, radiosensitizacija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: Z3-1873
• Name: Nov pristop žilno ciljane terapije, kjer z gensko terapijo utišamo dve neodvisni signalni poti, v kombinaciji z radioterapijo

• Funder: ARRS - Slovenian Research Agency
• Project number: P3-0003
• Name: Razvoj in ovrednotenje novih terapij za zdravljenje malignih tumorjev