Is there a critical tissue oxygen tension for bioenergetic status and cellular pH regulation in solid tumors?

Abstract

Bioenergetic and metabolic status have been correlated with tissue oxygenation in murine fibrosarcomas (FSaII) of varying sizes (44-600 mm3). Ratios of beta-nucleoside triphosphates to inorganic phosphate (beta NTP/P) and phosphocreatine to inorganic phosphate (PCr/P(i)) ratios derived from 31P nuclear magnetic resonance spectroscopy (NMR) were positively correlated to median tissue O2 tension (pO2) values using O2-sensitive needle electrodes. pH declined during growth with intracellular acidosis being evident in tumors > 350 mm3. Whereas lactic acid formation greatly contributed to this decline in small and medium-sized tumors, adenosine triphosphate (ATP) hydrolysis and slowing down of the activities of pumps involved in cellular pH regulation seem to be major factors responsible for intracellular acidification in bulky tumors. PCr levels decreased at an early growth stage, whilst ATP concentrations dropped in bulky malignancies only, coinciding with a decrease in adenylate energy charge and a substantial rise in the levels of total P(i). On average, median pO2 values of ca. 10 mmHg represent a critical threshold for energy metabolism. At higher median O2 tensions, levels of ATP, phosphomonoester (PME) and total P(i) were relatively constant. This coincided with intracellular alkalosis or neutrality and stable adenylate ratios. On average, median pO2 values < 10 mmHg coincided with intracellular acidosis, ATP depletion, a drop in energy charge and rising P(i) levels.