Evidence for differential viral oncolytic efficacy in an in vitro model of epithelial ovarian cancer metastasis.
Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses-Myxoma virus, double-deleted vaccinia virus, and Maraba virus-using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and with slightly slower kinetics in tumor spheroids. Myxoma virus and vaccinia viruses infect and kill adherent cells to a much lesser extent than Maraba virus, and their oncolytic potential is almost completely attenuated in spheroids. Myxoma virus and vaccinia are able to infect and spread throughout spheroids, but are blocked in the final stages of the lytic cycle, and oncolytic-mediated cell killing is reactivated upon spheroid reattachment. Alternatively, Maraba virus has a remarkably reduced ability to initially enter spheroid cells, yet rapidly infects and spreads throughout spheroids generating significant cell killing effects. We show that low-density lipoprotein receptor expression in ovarian cancer spheroids is reduced and this controls efficient Maraba virus binding and entry into infected cells. Taken together, these results are the first to implicate the potential impact of differential viral oncolytic properties at key steps of ovarian cancer metastasis.
Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada; Department of Anatomy & Cell Biology, Western University, London, Ontario, Canada.
Jessica G
JG
Tong
Translational Ovarian Cancer Research Program, London Regional Cancer Program , London, Ontario, Canada.
Yudith Ramos
YR
Valdes
Translational Head and Neck Cancer Research Program, London Regional Cancer Program , London, Ontario, Canada.
John W
JW
Barrett
Department of Medicine & Biochemistry, University of Ottawa, Ottawa, Ontario, Canada; Department of Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
John C
JC
Bell
Department of Pediatrics, University of Ottawa , Ottawa, Ontario, Canada.
David
D
Stojdl
Department of Molecular Genetics & Microbiology, University of Florida , Gainesville, Florida, USA.
Grant
G
McFadden
Department of Surgery, University of Toronto , Toronto, Ontario, Canada.
J Andrea
JA
McCart
Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada; Department of Biochemistry, Western University, London, Ontario, Canada; Department of Oncology, Western University, London, Ontario, Canada; Department of Obstetrics & Gynaecology, Western University, London, Ontario, Canada.
Gabriel E
GE
DiMattia
Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada; Department of Anatomy & Cell Biology, Western University, London, Ontario, Canada; Department of Oncology, Western University, London, Ontario, Canada; Department of Obstetrics & Gynaecology, Western University, London, Ontario, Canada.
Trevor G
TG
Shepherd