Breakthroughs and Views
Cancer metabolism: facts, fantasy, and fiction

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Abstract

The concept of a glycolytic cancer cell was introduced by Warburg over 70 years ago. This perception has since become the rationale that drives a considerable proportion of basic research on cancer, and it influences the current strategies for the diagnosis, monitoring, and treatment of cancer. Here we review the data from the last 40 years on this issue. We conclude that there is no evidence that cancer cells are inherently glycolytic, but that some tumours might indeed be glycolytic in vivo as a result of their hypoxic environment.

Section snippets

An energy budget

In order to address these questions, one needs, in a physiological environment, to measure at least oxygen consumption and lactate production. The oxygen consumption can be converted to a total oxidative ATP production. The lactate production can be converted directly to glycolytic ATP production and thus allows the total ATP production of a cell to be partitioned into its oxidative and anaerobic components.

We have termed these measurements a minimal energy budget, which quantifies total ATP

Perceptions of cancer metabolism; history and implications

Pioneering work on cancer metabolism was done by Warburg in 1929. These data were summarized by Warburg [2] and are shown in Table 1. Compared to liver and kidney cells of adult animals, mouse ascites cancer cells showed a dramatically increased contribution by glycolytic ATP turnover to total ATP production under air-saturated conditions. This phenomenon became known as the “Warburg effect” and is the origin of the perception that a high glycolytic rate is typical of cancer/transformed/tumour

Is the perception based on sound data?

The perception of a cancer metabolism obviously has had and is still having major and wide-ranging implications. But do the data on which this perception is based, satisfy the requirements for at least a minimal energy budget?

Warburg’s interpretation of his data was originally questioned by Weinhouse [22]. Weinhouse noted that the normoxic lactate production of normal cells such as brain, retina, kidney medulla, and intestinal mucosa was as high as that of many tumours, and that many tumours

A comparison between normal and cancer cells using only acceptable data

The only way to come to a rigorous conclusion on this issue of a specific cancer metabolism is to identify all energy budget studies that conform to at least the minimal standards, and use these data to compare the contributions of aerobic glycolysis to total ATP turnover in transformed and normal cells.

The acceptable data from a comprehensive, but not necessarily an exhaustive search of the literature, are summarized in Table 2a, Table 2b. The mean values for the glycolytic contribution to

The Pasteur rather than the Warburg effect. Cancers are glycolytic, but only because they are hypoxic

The majority of the data in Table 2a, Table 2b were produced in incubations that were saturated with room air at 37 °C; these incubations are termed normoxic. These conditions however are actually physiologically hyperoxic, as a 37 °C liquid saturated with room air has a pO2 of about 150 mm Hg, compared with the median pO2 of most tissues which ranges between 8 and 65 mm Hg [55]. This is an important consideration as there is good and increasing evidence that tumours are hypoxic in vivo. Vaupel et

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    Abbreviations: HIF, hypoxia inducible factor; FDG–PET, [18F]fluorodeoxyglucose positron emission tomography; Glut, glucose transporter; HK, hexokinase; VEGF, vascular endothelial growth factor; LDH, lactate dehydrogenase; pO2, oxygen partial pressure.

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