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
|Author:||Kujala, Anni1; Valkonen, Elina1; Sallinen, Hanna1,2,3;|
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
|Online Access:||PDF Full Text (PDF, 7.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2023062257864
|Publish Date:|| 2023-06-22
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.
Frontiers in medicine
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This study was supported by grants from the Finnish Academy, Kuopio University Hospital, Finnish Cancer Foundation, Orion Research Foundation, and Sigrid Juselius Foundation.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
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.