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The effects of hyperglycemia on glucose metabolism in epithelial ovarian cancer

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Title: The effects of hyperglycemia on glucose metabolism in epithelial ovarian cancer
Author: Kellenberger, Lisa Danielle
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: Petrik, James
Abstract: Glucose metabolism in cancer cells is uniquely adapted to maximize the production of both ATP and the precursors needed to support cell proliferation and tissue growth. Glycolysis, an anaerobic process normally limited by the presence of oxygen, proceeds at an elevated rate in both aerobic and anaerobic conditions. Glycolysis consumes large quantities of glucose while producing relatively small amounts of energy. The inefficiency of this process is not detrimental to the cell when glucose is abundant. However, evidence suggests that in cancer the normal concentration of circulating glucose does not meet the energy demands of the tumour and is therefore a limiting factor in cancer cell metabolism. Hyperglycemic conditions such as diabetes are becoming common comorbidities in cancer patients and are associated with increased risk and poorer prognosis of epithelial ovarian cancer (EOC). We hypothesise that elevated blood glucose permits tumour metabolism to function at maximal capacity thereby facilitating tumour growth and metastasis. The goal of this thesis was to examine the metabolic response and glucose transport kinetics of EOC in hyperglycemic environments. By inducing ovarian tumour growth in mouse models of Type 1 and Type 2 diabetes, we found that accelerated disease progression occurs in a glucose concentration-dependent manner. In addition, for the first time we show that EOC cells express not only the passive glucose transporters (GLUTs), but also a class of active glucose transporters, the sodium-glucose symporters (SGLTs). Glucose uptake into EOC cells in hyperglycemia is mediated by this sodium-dependent glucose transport. Surprisingly, SGLT2 appears to be a tumour suppressor: knockdown of SGLT2 in ovarian cancer cells increases the relative risk of death in tumour-bearing mice by more than 50 times. PET scans measuring accumulation of the glucose analogue fluoro-deoxyglucose (FDG) are a vital component of EOC treatment. However, FDG is a poor substrate for SGLTs, suggesting that current imaging fails to detect a large fraction of glucose transport into tumours. The use of SGLT-specific glucose analogues, particularly in patients with metabolic dysfunction, presents an opportunity to enhance the power of PET imaging and provide a more complete picture of tumour metabolism which may have therapeutic benefits.
Date: 2016-02
Rights: Attribution-NonCommercial-NoDerivs 2.5 Canada
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Attribution-NonCommercial-NoDerivs 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 2.5 Canada