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
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: email@example.com (NAR).