Seminar in PSA 106 at 3:40p.m.

ABSTRACT:

By Robert A. Gatenby

Cancer cells typically metabolize glucose anaerobically even in the presence of abundant oxygen. The inefficient energy production is compensated by increased flux, which is observed as a marked increase in the rate of glucose consumption. This phenomenon, first recognized by Warburg in the 1920's, forms the basis of FDG-PET imaging which has demonstrated significantly increased glucose uptake in the vast majority of human cancers in-vivo.

The cellular and microenvironmental dynamics leading to the emergence of the glycolytic phenotype during carcinogenesis remain unknown. Mathematical models adapted from population biology and evolutionary game theory demonstrate the glycolytic phenotype probably represents a successful adaptation to a Darwinian environment dominated by substrate competition during the later stages of the carcinogenesis.

A consequence of the glycolytic phenotype is increased excretion of acid and decreased extracellular pH (pHe) within tumors. The acid-mediated tumor invasion hypothesis proposes that this acidic microenvironment produces a proton gradient into peritumoral normal tissue resulting in a significant decrease in pHe. This significantly perturbs the normal tissue through: 1. loss of viability of normal cells because of acid pHe-induced increase in caspase activity resulting in cellular apoptosis via p53-dependent pathways. 2. extracellular matrix degradation due to release of Cathepsin B and other proteolytic enzymes and 3. promotion of angiogenesis through release of IL8 and VEGF. Tumor cells have an optimal pHe about 0.5 units lower than normal cells (pHe of about 6.8 for tumor cells vs. 7.35 for normal) and continue to proliferate. This allows the tumor edge to propagates into this space resulting in an invasive morphology. Thus, the altered tumor metabolism changes the tissue microenvironment so that it is optimal for transformed cells and lethal for normal tissue.

Diffusion-reaction and modified cellular automata models of acid-mediated tumor invasion produce tumor-host dynamics consistent with experimental and clinical observations. Specific clinical predictions include increased rate of tumor invasion and corresponding poor prognosis with increased glucose flux - an observation consistent with numerous studies from FDG-PET imaging.

The models predict mild systemic acidification may reduce the propagation velocity of the tumor edge and even destabilize the tumor fixed point solution. A decrease in the growth rate of experimental tumors following systemic acidification is demonstrated. Reanalysis of data from patients undergoing cytoreductive nephrectomy for metastatic renal cancer suggests this may represent a novel and successful clinical therapy.