title: Transgenic mice expressing inhibin α-subunit promoter (inhα)/Simian Virus 40 T-antigen (Tag) transgene as a model for the therapy of granulosa cell-derived ovarian cancer.
abstract: Granulosa cell tumors are rare, 3-7.6% of primary ovarian tumors, although with poor prognosis as the tumor-related mortality rate is 37.3%, with 80% of deaths occurring on recurrence. We have created a transgenic (TG) murine model for gonadal somatic cell tumors by expressing the powerful viral oncogene, Simian Virus 40 T-antigen (Tag), under the regulation of murine inhibin α-subunit 6 kb promoter (inhα/Tag). Gonadotropin dependent ovarian granulosa cell tumors were formed in females by the age of 5-6 months, with a 100% penetrance. We have successfully used the inhα/Tag model to test different treatment strategies for ovarian tumors. With a gene therapy trial in inhα/Tag mice crossbred with inhα/HSV-TK (herpes simplex virus thymidine kinase) mice (double TG), we proved the principle that targeted expression of HSV-TK gene in gonadal somatic cell tumors enabled tumor ablation by anti-herpes treatment. When we aimed at targeted destruction of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) expressing inhα/Tag tumor cells in vivo by a lytic peptide Hecate-CGβ conjugate, we could successfully kill the tumor cells, sparing the normal cells. We recently found high zona pellucida glycoprotein 3 (ZP3) expression in inhα/Tag granulosa cell tumors, as well as in human granulosa cell tumors. We tested the concept of treating the ovarian tumors of inhα/Tag mice by vaccination against the ectopically expressed ZP3. Immunotherapy with recombinant human (rh) ZP3 was highly successful with no objective side effects in inhα/Tag females, suggesting rhZP3 immunization as a novel strategy for the immunotherapy of ovarian granulosa cell tumors.
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Finland; Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Chrusciel
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Finland.
authors.forename: Milena
authors.initials: M
authors.lastname: Doroszko
authors.affiliation: Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Stelmaszewska
authors.affiliation: State Key Laboratory for Agrobiotechnology, China Agriculture University, Beijing, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ziecik
authors.affiliation: Pantarhei Bioscience B.V., Zeist, The Netherlands.
authors.forename: Herjan J T
authors.initials: HJ
authors.lastname: Coelingh-Bennink
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Finland; Institute of Reproductive and Developmental Biology (IRDB), Imperial College London, London, UK.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Finland; Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland. Electronic address: nafis.rahman@utu.fi.
authors.forename: Nafis A
authors.initials: NA
authors.lastname: Rahman
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006106:Granulosa Cell Tumor / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D007265:Inhibins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011401:Promoter Regions, Genetic; D013539:Simian virus 40 / Q000276:immunology
chemical_list: D000957:Antigens, Viral, Tumor; C094377:inhibin-alpha subunit; D007265:Inhibins
keywords: Gene therapy; Immunotherapy; Ovarian granulosa cell cancer; Targeted therapy; Therapeutic strategy; Transgenic murine model