High aerobic glycolysis in cancers: what does it mean?

Sirs

10.1038/nrc1478

With interest we have read the review by Gatenby and Gillies on high aerobic glycolysis in cancer¹. They state that “...widespread clinical use of ¹⁸fluorodeoxyglucose positron-emission tomography (FdG PET) has demonstrated that the glycolytic phenotype is observed in most human cancers.” However, we feel that “...the near-universal observation of aerobic glycolysis and its persistence even under normoxic conditions”¹ are misinterpretations of the real biochemical processes. In fact, only in the beginning is glycolysis in cancer cells aerobic, but later on it changes into mainly a 'fermentative' process.

Normally, the growth rate of all body cells is continuously under control. An essential feature of tumour cells is that they withdraw from growth regulation. The growth rate is determined by the nature of the regulatory derailment. In non-cancer cells catabolism is balanced with the energy need, and so with the oxygen supply. However, in a growing tumour angiogenesis will start, but the lead of the uncontrolled cancer cells is substantial and gives rise to an imbalance between an increasing energy need and a decreasing oxygen supply, resulting in a relative anaerobic or hypoxic condition. Consequently, the energy need is supplied by fermentative energy generation. Therefore, the imbalance increases and thus the fermentation with concomitant lactic-acid generation will increase.

The first step in the catabolic pathway — the glycolysis (Fig. 1) — implies that one mol of glucose is converted to 2 mol of pyruvic acid, with simultaneous production of 2 mol of ATP and 2 mol of NADH₂. Under aerobic conditions, the energy content of NADH₂, consisting of 3 mol of ATP per mol of NADH₂, is freed in the oxygen-dependent 'respiratory chain'. So the aerobic glycolysis yields 8 mol of ATP per mol of glucose. The dissimilation of one mol of pyruvic acid through the tricarbonic-acid cycle yields 15 mol of ATP, and so in total 38 mol of ATP are generated from one mol of glucose.

Figure 1: Energy generation in the absence of molecular oxygen.

The overall process of anaerobic glucose dissimilation consists of two processes: glycolysis from glucose to pyruvic acid, and fermentation of pyruvic acid to lactic acid. The absence of molecular oxygen causes the tricarbonic-acid cycle (TCAC) to be blocked and fermentation to occur.

Under hypoxic conditions, only a minor amount of oxygen is available. Therefore, the major part of the energy-rich electrons of glycolysis-related NADH₂ will be transferred by lactate dehydrogenase to pyruvic acid with lactic acid as a product (Fig. 1). Here, it is essential that the energy content of the NADH₂ molecules is not stored into ATP. The final result is that one mol of glucose yields only 2 mol of ATP by 'anaerobic' (or fermentative) glycolysis, instead of 8 molecules as by 'aerobic' glycolysis that only occurs as part of the oxidative energy generation.

In conclusion, if in a tumour the amount of supplied oxygen has become too low for complete aerobic dissimilation, the required energy will be generated by anaerobic dissimilation; that is, the anaerobic glycolysis. However, the faster solid tumours will ferment, the faster they will grow. Therefore, the upregulation of anaerobic glycolysis is more likely due to continuous induction rather than being constitutively expressed after one or more mutation(s) other than the mutation that causes the regulatory derailment.