Endotoxin-mediated necrosis and regression of established tumours in the mouse. A correlative study of quantitative changes in blood flow and ultrastructural morphology

Abstract

The fractional distribution of cardia output was measured in tumour-bearing mice treated with 50 micrograms intravenous endotoxin, and correlated with ultrastructural changes in tumour morphology. The proportion of the cardiac output going to the tumour decreased to less than 50% of its original value by 2 h and to 10%-30% by 6 h after giving endotoxin. Because endotoxin decreases absolute cardiac output, the actual perfusion of the tumour will be considerably less than these figures suggest. The decrease in perfusion correlated closely with changes in vascular morphology. Venous congestion on the tumour edge started within 1 h of giving endotoxin and by 3 h, endothelial damage and platelet aggregates were visible. At this time, all cells, tumour, connective tissue and infiltrate in the tumour centre were dead or damaged. By 24-48 h a conspicuous infiltrate of neutrophils and macrophages was present on the edge of the tumour and many of these cells were closely related to tumour cells. We suggest that the haemorrhagic necrosis may be caused by vascular obstruction leading to hypoxia and that the subsequent regression is mediated by activated macrophages and perhaps by neutrophils.