Altered glucose metabolism and the invasive tumor phenotype.

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 phenotypic heterogeneity of tumor populations suggests that a final cellular state common to all cancers may exist. Such a state must be the sequela of many possible genetic changes, and the cellular properties of the state must promote malignant, invasive growth. It is hypothesized 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 production 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 Spectroscopy (MRS). Application of mathematical models from population ecology 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 provide a simple but sufficient mechanism for invasive tumor growth. This hypothesis is testable experimentally and suggests significant new approaches to tumor therapy.