ALTERED GLUCOSE-METABOLISM AND THE INVASIVE TUMOR PHENOTYPE - INSIGHTS PROVIDED THROUGH MATHEMATICAL-MODELS (REVIEW)

Multiple genetic changes are necessary for carcinogenesis, yet a wide range of different genetic changes may give rise to malignant behavior and no set or sequence of defects is seen in all cancers. The similar pattern of invasive growth in malignancy despite the genotypic and ph enotypic heterogeneity of tumor populations suggests that a final cell ular state common to all cancers may exist. Such a state must be the s equela of many possible genetic changes, and the cellular properties o f the state must promote malignant, invasive growth. It is hypothesize d that the common denominator of the transformed state is reversion to primitive phenotype, and its invasive properties stem from alteration of metabolic pathways. Increased use of glycolysis and consequent pro duction of acid have been consistently demonstrated in malignant cells in vitro and are seen in the vast majority of clinical tumors imaged with FDG Positron Emission Tomography (PET) and Magnetic Resonance Spe ctroscopy (MRS). Application of mathematical models from population ec ology and competition theory demonstrates that these metabolic changes will alter the local microenvironment in ways that favor tumor growth but are lethal to normal cells. This phenomenon alone appears to prov ide a simple but sufficient mechanism for invasive tumor growth. This hypothesis is testable experimentally and suggests significant new app roaches to tumor therapy.