title: Ovarian tumor-initiating cells display a flexible metabolism.
abstract: An altered metabolism during ovarian cancer progression allows for increased macromolecular synthesis and unrestrained growth. However, the metabolic phenotype of cancer stem or tumor-initiating cells, small tumor cell populations that are able to recapitulate the original tumor, has not been well characterized. In the present study, we compared the metabolic phenotype of the stem cell enriched cell variant, MOSE-LFFLv (TIC), derived from mouse ovarian surface epithelial (MOSE) cells, to their parental (MOSE-L) and benign precursor (MOSE-E) cells. TICs exhibit a decrease in glucose and fatty acid oxidation with a concomitant increase in lactate secretion. In contrast to MOSE-L cells, TICs can increase their rate of glycolysis to overcome the inhibition of ATP synthase by oligomycin and can increase their oxygen consumption rate to maintain proton motive force when uncoupled, similar to the benign MOSE-E cells. TICs have an increased survival rate under limiting conditions as well as an increased survival rate when treated with AICAR, but exhibit a higher sensitivity to metformin than MOSE-E and MOSE-L cells. Together, our data show that TICs have a distinct metabolic profile that may render them flexible to adapt to the specific conditions of their microenvironment. By better understanding their metabolic phenotype and external environmental conditions that support their survival, treatment interventions can be designed to extend current therapy regimens to eradicate TICs.
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Anderson
authors.affiliation: Biomedical Science and Pathobiology, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Roberts
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Madlyn I
authors.initials: MI
authors.lastname: Frisard
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, USA. Electronic address: hulvermw@vt.edu.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hulver
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, USA. Electronic address: eschmelz@vt.edu.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmelz
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010101:Oxygen Consumption; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D019344:Lactic Acid; D005947:Glucose
keywords: AICAR; Glycolytic phenotype; Metabolism; Metformin; Ovarian cancer microenvironment; Tumor-initiating cell