Characterization of Metabolic Differences in Benign, Slow Developing and Tumor Initiating Ovarian Cancers

Ovarian cancer is known as the "silent killer," due to its late diagnosis and frequent recurrence after initial treatment. Finding a new way to diagnose and treat ovarian cancer in conjunction with current therapies is paramount. By capitalizing on metabolic changes that occur during cancer progression, interventions can be developed. The Nobel laureate Otto Warburg is credited with discovering an altered metabolic state within cancer cells known as the Warburg effect. In the Warburg effect, cancer cells participate in an increased rate of aerobic glycolysis with an excess secretion of lactate, allowing for carbon flux into biosynthetic pathways. Exactly which metabolic pathways are altered in ovarian cancer and at which stage in the progression of ovarian cancer they are occurring was unknown. Therefore using the recently established mouse ovarian surface epithelial (MOSE) progression model, we were able to measure metabolic changes in varying states of disease and levels of aggressiveness. As cells progressed from a benign early stage (MOSE-E), through a transitional intermediate stage (MOSE-I), to an aggressive late stage (MOSE-L), the MOSE cells became more glycolytic and lipogenic, establishing the MOSE model as a valuable model for studying ovarian cancer metabolism. Treating the MOSE cells with the naturally occurring chemotherapeutic agent sphingosine decreased p-AKT protein levels in the cell, decreased the glycolytic rate and decreased de novo cholesterol synthesis. Cancer stem cells are known to be resistant to chemotherapy treatments and targeting their metabolism may be promising for combinatorial treatments. Therefore, the metabolism of highly aggressive tumor-initiating cells (TIC), harvested from ascites of C57Bl/6 mice injected with MOSE-L cells were characterized. Although the basal metabolism of the TICs was similar to the MOSE-L cells, TICs were more resistant to cell death as a consequence of external stresses and substrate depletion. The TICs could also up-regulate oxygen consumption rate (OCR) when uncoupled and increase glycolysis when ATP Synthase was inhibited, highlighting their resiliency. Taken together, we have identified targets for treatment strategies that could suppress the growth of primary tumors and may be effective against TICs, thereby suppressing tumor recurrence and possibly prolonging the life of women with ovarian cancer.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Human Nutrition, Foods, and Exercise

Department dc:contributor.department

Human Nutrition, Foods, and Exercise

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2013

Author dc:creator

• Anderson, Angela S.

Chairs dc:contributor.committeechair

• Schmelz, Eva M.
• Hulver, Matthew W.

Committee members dc:contributor.committeemember

• Roberts, Paul C.
• Frisard, Madlyn I.

• Ovarian cancer
• metabolism
• Warburg effect
• cancer stem cells
• mitochondria

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:733

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/50812