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Kujala A, Valkonen E, Sallinen H, Tuppurainen L, Laakso H, Ylä-Herttuala E, Liimatainen T, Kujala J, Jokelainen O, Sironen R, Anttila M and Ylä-Herttuala S (2022) AAV8-mediated sVEGFR2 and sVEGFR3 gene therapy combined with chemotherapy reduces the growth and microvasculature of human ovarian cancer and prolongs the survival in mice. Front. Med. 9:1018208. doi: 10.3389/fmed.2022.1018208

AAV8-mediated sVEGFR2 and sVEGFR3 gene therapy combined with chemotherapy reduces the growth and microvasculature of human ovarian cancer and prolongs the survival in mice

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Author: Kujala, Anni1; Valkonen, Elina1; Sallinen, Hanna1,2,3;
Organizations: 1Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
2Department of Gynecology, Kuopio University Hospital, Kuopio, Finland
3School of Medicine, Gynecology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
4A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
5Clinical Imaging Center, Kuopio University Hospital, Kuopio, Finland
6Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu, Finland
7Department of Diagnostic Radiology, Oulu University Hospital, Oulu, Finland
8Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
9Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
10Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 7.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2023062257864
Language: English
Published: Frontiers Media, 2022
Publish Date: 2023-06-22
Description:

Abstract

Background: Vascular endothelial growth factors (VEGFs) are major regulators of intratumoral angiogenesis in ovarian cancer (OVCA). Overexpression of VEGFs is associated with increased tumor growth and metastatic tendency and VEGF-targeting therapies are thus considered as potential treatments for OVCA. Here, we examined the antiangiogenic and antitumoral effects on OVCA of adeno-associated virus 8 (AAV8)-mediated expression of soluble VEGF receptors (sVEGFRs) sVEGFR2 and sVEGFR3 together with paclitaxel and carboplatin chemotherapy.

Materials and methods: Immunodeficient mice were inoculated with human OVCA cell line SKOV-3m. Development of tumors was confirmed with magnetic resonance imaging (MRI) and mice were treated with gene therapy and paclitaxel and carboplatin chemotherapy. The study groups included (I) non-treated control group, (II) blank control vector AAV8-CMV, (III) AAV8-CMV with chemotherapy, (IV) AAV8-sVEGFR2, (V) AAV8-sVEGFR3, (VI) AAV8-sVEGFR2 and AAV8-sVEGFR3, and (VII) AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy. Antiangiogenic and antitumoral effects were evaluated with immunohistochemical stainings and serial MRI.

Results: Reduced intratumoral angiogenesis was observed in all antiangiogenic gene therapy groups. The combined use of AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy suppressed ascites fluid formation and tumor growth, thus improving the overall survival of mice. Antitumoral effect was mainly caused by AAV8-sVEGFR2 while the benefits of AAV8-sVEGFR3 and chemotherapy were less prominent.

Conclusions: Combined use of the AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy reduces intratumoral angiogenesis and tumor growth in OVCA mouse model. Results provide preclinical proof-of-concept for the use of soluble decoy VEGFRs and especially the AAV8-sVEGFR2 in the treatment of OVCA.

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Series: Frontiers in medicine
ISSN: 2296-858X
ISSN-E: 2296-858X
ISSN-L: 2296-858X
Volume: 9
Article number: 1018208
DOI: 10.3389/fmed.2022.1018208
OADOI: https://oadoi.org/10.3389/fmed.2022.1018208
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3111 Biomedicine
Subjects:
MRI
angiogenesis
antiangiogenic
lymphangiogenesis
ovarian cancer
xenograft
Article
Funding: This study was supported by grants from the Finnish Academy, Kuopio University Hospital, Finnish Cancer Foundation, Orion Research Foundation, and Sigrid Juselius Foundation.
Dataset Reference: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Copyright information: Copyright © 2022 Kujala, Valkonen, Sallinen, Tuppurainen, Laakso, Ylä-Herttuala, Liimatainen, Kujala, Jokelainen, Sironen, Anttila and Ylä-Herttuala. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
  https://creativecommons.org/licenses/by/4.0/