title: Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium.
abstract: Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer.
authors.affiliation: Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia.
authors.forename: Preety
authors.initials: P
authors.lastname: Bajwa
authors.affiliation: Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia.
authors.forename: Prathima B
authors.initials: PB
authors.lastname: Nagendra
authors.affiliation: Hunter Cancer Biobank, New South Wales, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nielsen
authors.affiliation: Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia.
authors.forename: Subhransu S
authors.initials: SS
authors.lastname: Sahoo
authors.affiliation: Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Bielanowicz
authors.affiliation: School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.|Division of Gynaecology Oncology, Department of Medical Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia.
authors.forename: Janine M
authors.initials: JM
authors.lastname: Lombard
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: J Erby
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia.
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Tanwar
mesh_terms: D000375:Aging; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D020123:Sirolimus
keywords: Gerotarget; OSE; mTOR; ovarian aging; ovary; rapamycin