TUMOR MICROENVIRONMENT - CHARACTERIZATION AND SIGNIFICANCE FOR HYPERTHERMIA TREATMENT

The complex (patho-)physiological events accompanying heating of tumor tissues have been reviewed, with particular emphasis on the changes i n blood flow, oxygenation, metabolic and bioenenergetic status. In hum an tumors, pronounced heterogeneity is seen in rates of blood flow, an d flow changes upon heating are unpredictable and spatially and tempor ally variable. Flow increases in some cases may result in improved hea t dissipation such that therapeutically relevant temperatures may not be achieved. Tumor oxygenation changes tend to reflect alterations in blood flow during hyperthermia with increases in oxygenation followed by a return to baseline levels being reported for some human and exper imental tumors, at least upon moderate hyperthermia. Also, a large amo unt of variation is seen in changes in tumor glucose levels upon hyper thermia, although these appear to be related to changes in blood flow and the development of interstitial edema. Lactate levels increase upo n hyperthermia as a result of intensified glycolysis. Tumor pH (both i ntra- and extracellular) decrease upon high-dose hyperthermia, with su bsequent recovery depending on the dose of hyperthermia delivered. Tum or bioenergetic status worsens during hyperthermia, as evidenced by de creases in ATP and phosphocreatine and increases in inorganic phosphat e. ATP hydrolysis results in an accumulation of the purine catabolites hypoxanthine, xanthine and uric acid and proton formation, which may in turn contribute to a heat-induced acidosis. Additionally, the forma tion of highly reactive oxygen species may contribute to heat induced cytotoxicity.