Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized (13)C-pyruvate.

RATIONALE AND OBJECTIVES: Cancer cells generate more lactate than normal cells under both aerobic and hypoxic conditions-exhibiting the so-called Warburg effect. However, the relationship between the Warburg effect and tumor metastatic potential remains controversial. We intend to investigate whether the higher lactate reflects higher tumor metastatic potential. MATERIALS AND METHODS: We used hyperpolarized (13)C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate (13)C-labeling in vivo in mouse xenografts of the highly metastatic (MDA-MB-231) and the relatively indolent (MCF-7) human breast cancer cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of data analysis including the differential equation fit, q-ratio fit, and ratio fit methods. RESULTS: Consistent results from the three methods showed that the highly metastatic tumors exhibited a smaller apparent forward rate constant (k(+) = 0.060 ± 0.004 s(-1)) than the relatively indolent tumors (k(+) = 0.097 ± 0.013 s(-1)). The ratio fit generated the greatest statistical significance for the difference (P = .02). No significant difference in the reverse rate constant was found between the two tumor lines. CONCLUSIONS: The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected (13)C-pyruvate and supports the notion that breast tumor metastatic risk is not necessarily associated with the high levels of glycolysis and lactate production. More studies are needed to confirm whether and how much the measured apparent rate constants are affected by the membrane transporter activity and whether they are primarily determined by the LDH activity.

Brown adipose tissue glyceroneogenesis is activated in rats exposed to cold.

We have previously found that glyceroneogenesis is very active in brown adipose tissue (BAT) and increases in fasted, diabetic and high-protein-diet-fed rats, situations of reduced thermogenic activity. To understand better the role of glyceroneogenesis in BAT glycerol-3-phosphate (G3P) generation, we investigated its activity during cold exposure (10 days at 4 degrees C), a condition in which, in contrast to the above situations, BAT thermogenesis is markedly activated. Rates of total (from all sources) BAT fatty acid (FA) synthesis and rates of incorporation of glucose carbon into BAT glyceride-FA and -glycerol in vivo were markedly increased by cold exposure. Cold exposure induced a marked increase in BAT glyceroneogenic activity, evidenced by (1) increased rates of non-glucose carbon incorporation into glyceride-glycerol in vivo and of [1-14C]-pyruvate incorporation into glyceride-glycerol in vitro, and (2) a threefold increase in phosphoenolpyruvate carboxykinase activity. Most of the glyceride-glycerol synthesized by BAT via glyceroneogenesis or from glucose was used to esterify preformed FA. This use was markedly increased by cold exposure, in parallel with a pronounced activation of BAT lipoprotein lipase activity. In conclusion, during cold exposure BAT glyceroneogenesis is markedly activated, contributing to increase the generation of G3P, which is mostly used to esterify preformed FA.

Control of glyceroneogenic activity in rat brown adipose tissue.

Brown adipose tissue (BAT) glyceroneogenesis was evaluated in rats either fasted for 48 h or with streptozotocin-diabetes induced 3 days previously or adapted for 20 days to a high-protein, carbohydrate-free (HP) diet, conditions in which BAT glucose utilization is reduced. The three treatments induced an increase in BAT glyceroneogenic activity, evidenced by increased rates of incorporation of [1-14C]pyruvate into triacylglycerol (TAG)-glycerol in vitro and a marked, threefold increase in the activity of BAT phosphoenolpyruvate carboxykinase (PEPCK). BAT glycerokinase activity was not significantly affected by fasting or diabetes. After unilateral BAT denervation of rats fed either the HP or a balanced diet, glyceroneogenesis activity increased in denervated pads, evidenced by increased rates of nonglucose carbon incorporation into TAG-glycerol in vivo (difference between 3H2O and [14C]glucose incorporations) and of [1-14C]pyruvate in vitro. PEPCK activity was not significantly affected by denervation. The data suggest that BAT glyceroneogenesis is not under sympathetic control but is sensitive to hormonal/metabolic factors. In situations of reduced glucose use there is an increase in BAT glyceroneogenesis that may compensate the decreased generation of glycerol-3-phosphate from the hexose.