Modulation of Mammary Stromal Cell Lactate Dynamics by Ambient Glucose and Epithelial Factors

Abstract

Hyperglycemia is a risk factor for a variety of human cancers. Increased access to glucose and that tumor metabolize glucose by a glycolyticprocess even in the presence of oxygen (Warburg effect), provide a framework to analyze a particular set of metabolic adaptationmechanisms that may explain this phenomenon. In the present work, using a mammary stromal cell line derived from healthy tissue that wassubjected to a long-term culture in low (5 mM) or high (25 mM) glucose, we analyzed kinetic parameters of lactate transport using a FRETbiosensor. Our results indicate that the glucose pre-culture and soluble epithelial factors constitute a stimulus for lactate stromalproduction, factors that also modify the kinetic parameters and the monocarboxylate transporters expression in stromal cells. We alsoobserved a vectorialflux of lactate from stroma to epithelial cells in a co-culture setting and found that the uptake of lactate by epithelialcells correlates with the degree of malignancy. Glucose preconditioning of the stromal cell stimulated epithelial motility. Ourfindingssuggest that lactate generated by stromal cells in the high glucose condition stimulate epithelial migration. Overall, our results support thenotion that glucose not only provides a substrate for tumor nutrition but also behaves as a signal promoting malignancy.