Pre-Clinical and Clinical Investigation of the Impact of Obesity on Ovarian Cancer Pathogenesis
Technical Report,25 Sep 2012,24 Sep 2015
University of North Carolina at Chapel Hill Chapel Hill United States
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The metabolic consequences of obesity may be critical in the development of ovarian cancer OC, resulting in biologically different cancers than those that arise in leaner women. This may occur through aberrant modulation of mTOR signaling, given that alterations in this pathway are common in both obesity and OC. We found that OCs arising in obese versus lean mice and women have distinct gene expression profiles, involving many metabolically relevant genes and pathways. In addition, diet induced-obesity promoted tumor growth in a genetically engineered mouse model of OC, coincident with mitochondrial dysfunction and energy supplied by fatty acid oxidation rather than glycolysis in tumors from obese versus lean mice. MetforminAMPK activator but not everolimus mTOR inhibitor was more efficacious in the inhibition of tumor growth in obese versus lean mice. Metformins increased efficacy in the obese setting corresponded with inhibition of mitochondrial complex 1, halting of fatty acid oxidation and stimulation of glycolysis in only tumors from obese mice. For our in vitro studies, metformin and everolimus had similar effects on proliferation, inhibition of mTOR signaling and glycolysis but opposite effects on glucose uptake, which may also contribute to metformins enhanced anti-tumorigenic effects in the setting of obesity.