Tumour thermotolerance, a physiological phenomenon involving vessel normalisation.

The purpose of this study was to delineate the mechanisms by which stromal components of cancer may induce tumour thermotolerance and exploit alterations in stromal and tumour physiology to enhance radiation therapy. The vascular thermoresponse was monitored by daily one-hour 41.5°C heatings in two murine solid tumour models, SCK murine mammary carcinoma and B16F10 melanoma. A transient increase was seen in overall tumour oxygenation for 2-3 days, followed by a progressive decline in tumour pO(2) upon continued daily heatings. Vascular thermotolerance was further studied by treating tumours with different heating strategies, i.e. (1) a single 60 min 41.5°C treatment; (2) two consecutive daily treatments of 41.5°C for 60 min; (3) a single 60 min 43°C treatment or (4) two days of 41.5°C for 60 min followed by treatment with 43°C for 60 min on the third day. Pre-heating tumours with mild temperature hyperthermia induced vascular thermotolerance, which was accompanied by evidence of vessel normalisation, i.e. a decrease in microvessel density and an increase in pericyte coverage. Rational scheduling of fractionated radiation during heat-induced increases in tumour oxygen levels rendered a significantly greater, synergistic, tumour growth inhibition. In vitro clonogenic survival responses of the individual cell types associated (endothelial cells, fibroblasts, pericytes and tumour cells) indicated only a direct cellular thermotolerance in endothelial cells. Overall, this suggests that tumour thermotolerance is a physiological phenomenon mediated through improvement of functional vasculature.