Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium

Preety Bajwa, Prathima B. Nagendra, Sarah Nielsen, Subhransu S. Sahoo, Amanda Bielanowicz, Janine M. Lombard, J. Erby Wilkinson, Richard A. Miller and Pradeep S. Tanwar _

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Oncotarget. 2016; 7:19214-19227. https://doi.org/10.18632/oncotarget.8468

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Abstract

Preety Bajwa1, Prathima B. Nagendra1, Sarah Nielsen2, Subhransu S. Sahoo1, Amanda Bielanowicz1, Janine M. Lombard3,4, J. Erby Wilkinson5, Richard A. Miller6 and Pradeep S. Tanwar1

1 Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia

2 Hunter Cancer Biobank, New South Wales, Australia

3 School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia

4 Division of Gynaecology Oncology, Department of Medical Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia

5 Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA

6 Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA

Correspondence to:

Pradeep S. Tanwar, email:

Keywords: ovarian aging, rapamycin, mTOR, ovary, OSE, Gerotarget

Received: February 04, 2016 Accepted: March 23, 2016 Published: March 29, 2016

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.


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