Hyperglycemia promotes insulin-independent ovarian tumor growth

Abstract

Introduction: Epithelial ovarian cancer (EOC) is notoriously difficult to diagnose in its earlier and more treatable stages, making it one of the deadliest cancers in women. Comorbid diabetes is associated with poor prognosis in EOC and pro-growth insulin signalling is often considered to be the driving factor. However, EOC cells are also highly glycolytic and insulin-independent glucose uptake is essential to their metabolism. Evidence of gluconeogenesis in cancer in vivo suggests that the normal concentration of circulating glucose does not meet the energy demands of the tumor and may therefore be a limiting factor in cancer cell metabolism. Diabetics have elevated blood glucose that has the potential to meet these energy demands and facilitate cancer progression.

Methods: To determine whether hyperglycemia is a potentially modifiable factor independent of insulin, orthotopic ovarian tumors were induced in mice with acute Type 1 (hypo-insulinemic) or Type 2 (hyper-insulinemic) diabetes.

Results: Hyperglycemia accelerated the growth of ovarian tumors in a glucose concentration-dependent manner and significantly shortened overall survival. Reciprocally, the presence of a tumor improved impaired glucose tolerance in both Type 1 and Type 2 diabetes. In mice with chronic Type 1 diabetes, hyperglycemia limited tumor growth without changing overall survival, indicating that systemic metabolic stress can accelerate time to death independent of primary tumor size. When modeled in vitro, long-term culture in 25mM vs 6mM glucose resulted in significantly different growth and metabolism.

Conclusions: Taken together, this study shows that systemic metabolic disturbances can have a profound impact on both the growth of ovarian tumors and on overall survival.

Keywords: Diabetes; Glucose; Hyperglycemia; Ovarian cancer; Warburg effect.