Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity.

Abstract

Solid tumors have been observed to develop an acidic extracellular environment, which is believed to occur as a result of lactic acid accumulation produced during aerobic and anaerobic glycolysis. Experiments using glycolysisdeficient ras-transfected Chinese hamster lung fibroblasts have been performed to test the hypothesis that lactic acid production within solid tumors is responsible for the development of tumor acidity. The variant cells have defects in glucose transport and in the glycolytic enzyme phosphoglucose isomerase with 1% activity compared to parental cells. Consequently, the in vitro rate of lactic acid production by variant cells was <4% compared to parental cells. An in vitro correlation between lactic acid production and acidification of exposure medium was observed for parental and variant cells. Implantation of both cell lines into nude mice led to tumors with minimal difference in growth rate. As expected, variant cells died when exposed to hypoxic conditions in culture, and parental tumors were observed to have a larger fraction of cells resistant to radiation due to hypoxia (27%) than variant tumors (2%). Using pH microelectrodes, parental (n = 12) and variant (n = 12) tumors were observed to have extracellular pH (pH) values of 6.65 ± 0.07 and 6.78 ± 0.04 (mean ± SE, P = 0.13), respectively, whereas normal muscle had a pH. of 7.29 ± 0.06 (P < 0.0001 for both cell lines). The lactic acid content of variant tumors was found to be similar to that in serum, whereas parental tumors had lactic acid content that was higher than in serum (P < 0.0001). We conclude that there was no correlation between lactic acid content and acidosis for these tumors derived from ras-transfected fibroblasts. These results provide evidence that the production oflactic acid via glycolysis is not the only mechanism responsible for the development of an acidic environment within solid tumors.

The relationship between extracellular lactate and tumour pH in a murine tumour model of ischaemia-reperfusion

“…It should be noted that within a particular tumour there may be a correlation between LACTe and PHe following an intervention such as ischaemia; however, it is clear that PH-of different types of tumours may depend on factors other than LACTe. This is emphasized by a recent study using ras-transfected fibroblast cells, which are glycolysis deficient (Newell et al, 1993). These variant cells produce approximately 1% of the parental line's production of lactic acid but have similar PHe (pHe = 6.78 ± 0.04) compared with the parental line (pH.e= 6.65 ± 0.07) when grown in vivo.…”

“…Thus, if extracellular pH correlates with lactate levels, it might be a useful predictor for such biological effects. However, the simple assumption that lactate is a major determinant of extracellular pH has been challenged by the finding that transfected cells, which cannot produce lactate, still develop an acidic extracellular milieu (Newell et al, 1993). We have investigated the relationship between extracellular lactate (LACTe) and PH.…”

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

“…Carbonic acid/bicarbonate axis. In the tumor microenvironment, there is poor catabolite removal by the inefficient and abnormal blood vessels, leading to accumulation of CO 2 [Newell et al, 1993;Helmlinger et al, 2002]. The discovery of the effect on intracellular pH of angiostatin was manifested in experiments where the extracellular pH was either lowered by lowering the bicarbonate to 7 mM at 5% CO 2 , or by raising the CO 2 to 17% and keeping the bicarbonate at 26 mM.…”

Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients

“…Using glycolysis-deficient cells (Pouyssegur et al, 1980), the simultaneous knowledge of pH/pO2 may help determine the origin of non-glycolytic acidification, as reported in some tumours (Hwang et al, 1992;Newell et al, 1993). Abbreviations BCECF, 2',7'-bis-(2-carboxyethyl)-5,6-carboxyfluorescein; FRIM, fluorescence ratio imaging; PIOS; pinhole iUlumination and optical sectioning; RBC, red blood ceUl; SCID, severe combined immunodeficient.…”