The Role of Dysregulated Glucose Metabolism in Epithelial Ovarian Cancer

Kellenberger, Lisa D.; Bruin, Jennifer E.; Greenaway, James; Campbell, Nicole; Moorehead, Roger A.; Holloway, Alison C.; Petrik, Jim

doi:10.1155/2010/514310

Cited by 54 publications

(44 citation statements)

References 122 publications

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“…40 Hyperinsulinemia and the resulting increase in bioavailable insulinlike growth factor 1 (IGF-1) may play an important role in neoplastic transformation. 41 Binding of IGF-1 to the IGF-1 receptor activates cell cycle progression and promotes cell growth. In addition, insulin affects tumorigenesis indirectly by reducing the level of IGF-binding protein 1, further increasing the levels of circulating IGF-1.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus and Ovarian Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies

Lee

Jeon

Kim

et al. 2013

Int J Gynecol Cancer

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Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus and Ovarian Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies

Lee

Jeon

Kim

et al. 2013

Int J Gynecol Cancer

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“…Diabetic hyperglycemia is often associated with cancer predisposition [99,100] and may be a driving force for the metabolic shift observed in treated blastocysts [101]. However, even if embryonic cells could adapt their metabolism through a common mechanism with cancer cells, it is likely that, at some point, early development would avoid a tumor fate.…”

Section: Discussionmentioning

confidence: 99%

Differential Gene Expression Profile in Bovine Blastocysts Resulting from Hyperglycemia Exposure During Early Cleavage Stages1

Cagnone

Dufort

Vigneault

et al. 2012

Biology of Reproduction

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To understand the compromised survival of embryos derived from assisted reproductive techniques, transcriptome survey of early embryonic development has shown the impact of in vitro culture environment on gene expression in bovine or other living species. However, how the differentially expressed genes translate into developmentally compromised embryos is unresolved. We therefore aimed to characterize transcriptomic markers expressed by bovine blastocysts cultured in conditions that are known to impair embryo development. As increasing glucose concentrations has been shown to be stressful for early cleavage stages of mammalian embryos and to decrease subsequent blastocyst survival, in vitro-matured/fertilized bovine zygotes were cultured in control (0.2 mM) or high-glucose (5 mM) conditions until the 8- to 16-cell stage, and then transferred to control media until they reached the blastocyst stage. The concentration of 5 mM glucose was chosen as a stress treatment because there was a significant effect on blastocyst rate without the treatment's being lethal as with 10 mM. Microarray analysis revealed gene expression differences unrelated to embryo sex or hatching. Overrepresented processes among differentially expressed genes in treated blastocysts were extracellular matrix signalling, calcium signaling, and energy metabolism. On a pathophysiological level, higher glucose treatment impacts pathways associated with diabetes and tumorigenesis through genes controlling the Warburg effect, i.e., emphasis on use of anaerobic glycolysis rather than oxidative phosphorylation. These results allowed us to conclude that disruption of in vitro preattachment development is concomitant with gene expression modifications involved in metabolic control.

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“…This phenomenon is now known as the "Warburg effect" and has been observed in various types of cancers, including ovarian cancer (14). For example, 2-deoxy-D-glucose, a glucose analog, has been shown to be effective as an anticancer treatment in several cancers, including ovarian cancer in vitro (42).…”

mentioning

confidence: 99%

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration

Caneba

Bellancé

Yang

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Anoikis resistance, or the ability for cells to live detached from the extracellular matrix, is a property of epithelial cancers. The "Warburg effect," or the preference of cancer cells for glycolysis for their energy production even in the presence of oxygen, has been shown to be evident in various tumors. Since a cancer cell's metastatic ability depends on microenvironmental conditions (nutrients, stromal cells, and vascularization) and is highly variable for different organs, their cellular metabolic fluxes and nutrient demand may show considerable differences. Moreover, a cancer cell's metastatic ability, which is dependent on the stage of cancer, may further create metabolic alterations depending on its microenvironment. Although recent studies have aimed to elucidate cancer cell metabolism under detached conditions, the nutrient demand and metabolic activity of cancer cells under nonadherent conditions remain poorly understood. Additionally, less is known about metabolic alterations in ovarian cancer cells with varying invasive capability under anoikis conditions. We hypothesized that the metabolism of highly invasive ovarian cancer cells in detachment would differ from less invasive ovarian cancer cells and that ovarian cancer cells will have altered metabolism in detached vs. attached conditions. To assess these metabolic differences, we integrated a secretomics-based metabolic footprinting (MFP) approach with mitochondrial bioenergetics. Interestingly, MFP revealed higher pyruvate uptake and oxygen consumption in more invasive ovarian cancer cells than their less invasive counterparts. Furthermore, ATP production was higher in more invasive vs. less invasive ovarian cancer cells in detachment. We found that pyruvate has an effect on highly invasive ovarian cancer cells' migration ability. Our results are the first to demonstrate that higher mitochondrial activity is related to higher ovarian cancer invasiveness under detached conditions. Importantly, our results bring insights regarding the metabolism of cancer cells under nonadherent conditions and could lead to the development of therapies for modulating cancer cell invasiveness. oxidative phosphorylation; metabolomics; Warburg effect; bioenergetics; cancer migration and anoikis OVARIAN CANCER REMAINS A LEADING CAUSE of gynecological malignancy-related deaths and is often detected in the late stages, when the cancer has already metastasized (5). Of all ovarian cancer diagnoses, most are classified as epithelial ovarian carcinoma (17). In the process of epithelial ovarian cancer metastasis, cancer cells can remain viable while they are suspended in peritoneal fluid in the peritoneal cavity. A normal epithelial cell would in this environment undergo anoikis or epithelial cell death due to detachment, first coined by Frisch and Francis (8) in 1994. However, cancer cells, including ovarian cancer cells, can survive without extracellular matrix attachment and are thus considered anoikis resistant. Anoikis resistance in cancer has been widely studied from t...

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The Role of Dysregulated Glucose Metabolism in Epithelial Ovarian Cancer

Cited by 54 publications

References 122 publications

Diabetes Mellitus and Ovarian Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies

Diabetes Mellitus and Ovarian Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies

Differential Gene Expression Profile in Bovine Blastocysts Resulting from Hyperglycemia Exposure During Early Cleavage Stages1

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration

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