Mathematical Modeling of the Function of Warburg Effect in Tumor Microenvironment.

Tumor cells are known for their increased glucose uptake rates even in the presence of abundant oxygen. This altered metabolic shift towards aerobic glycolysis is known as the Warburg effect. Despite an enormous number of studies conducted on the causes and consequences of this phenomenon, little is known about how the Warburg effect affects tumor growth and progression. We developed a multi-scale computational model to explore the detailed effects of glucose metabolism of cancer cells on tumorigenesis behavior in a tumor microenvironment. Despite glycolytic tumors, the growth of non-glycolytic tumor is dependent on a congruous morphology without markedly interfering with glucose and acid concentrations of the tumor microenvironment. Upregulated glucose metabolism helped to retain oxygen levels above the hypoxic limit during early tumor growth, and thus obviated the need for neo-vasculature recruitment. Importantly, simulating growth of tumors within a range of glucose uptake rates showed that there exists a spectrum of glucose uptake rates within which the tumor is most aggressive, i.e. it can exert maximal acidic stress on its microenvironment and most efficiently compete for glucose supplies. Moreover, within the same spectrum, the tumor could grow to invasive morphologies while its size did not markedly shrink.