Microenvironmental and cellular consequences of altered blood flow in tumours.

Tumour angiogenesis is triggered by various signals characteristic of the tumour microenvironment, including low oxygen tension, low extracellular pH and low glucose concentration. Tumour microvasculature is chaotic, producing perfusion heterogeneities which can be visualized by MRI and other modalities. Inefficient perfusion in tumours produces regions of transient and chronic hypoxia. Tumour hypoxia is associated with adverse clinical outcomes and reduced patient survival. Hypoxia may be a factor in activation of extracellular matrix-degrading proteases, and some studies have correlated primary tumour hypoxia with likelihood of tumour cell dissemination. Exposure to hypoxia either induces or selects for cells that are hyperglycolytic, and this in turn produces local acidosis which is also a common feature of solid tumours. Increased glucose uptake in hyperglycolyzing tumour cells is the basis of lesion-visualization in positron emission tomography using 18F-fluorodeoxyglucose. Tumour acidity can reduce the effectiveness of weak-base drugs, but can be exploited to increase the anti-tumour activity of weak-acid chemotherapeutics. Evidence linking tumour acidity with increased activity of several extracellular matrix-degrading enzyme systems is examined. High levels of lactate, another end-product of glycolysis, in primary lesions have been correlated with increased likelihood of metastasis. In the numerous studies correlating hypoxia, acidity and lactate with metastasis, the direction of the causality has not been adequately established. We hypothesize that adoption of a hyperglycolytic phenotype is a necessary feature of carcinogenesis itself, and confers a survival and proliferative advantage to tumour cells over surrounding normal cells. Empirical evidence supporting this "acid-mediated tumour invasion" model is discussed.