An official journal of the Society for Biology of Reproduction and the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn

March 2014 (No. 1)

Transgenic mice expressing inhibin a-subunit promoter (inha)/Simian Virus 40 T-antigen (Tag) transgene as a model for the therapy of granulosa cell-derived ovarian cancer

Marcin Chrusciel a,b, Milena Doroszko a, Joanna Stelmaszewska c, Xiangdong Li d, Adam J. Ziecik b, Herjan J.T. Coelingh-Bennink e, Ilpo Huhtaniemi a,f, Nafis A. Rahman a,c,*

a Department of Physiology, Institute of Biomedicine, University of Turku, Finland

b Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland

c Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland

d State Key Laboratory for Agrobiotechnology, China Agriculture University, Beijing, China

e Pantarhei Bioscience B.V., Zeist, The Netherlands

f Institute of Reproductive and Developmental Biology (IRDB), Imperial College London, London, UK

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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 a-subunit 6 kb promoter (inhα/Tag). Gonadotro- pin 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 inha/Tag model to test different treatment strategies for ovarian tumors. With a gene therapy trial in inhα/ Tag mice crossbred with inha/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-CGb 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.

Reproductive Biology 2014 14 1: 25-31

* Corresponding author: Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; e-mail address: (NAR).