For decades, FDG (18F-fluorodeoxyglucose) imaging has been a standard clinical method for diagnosing and monitoring cancer. But new research harnessing the technique has challenged what we know about how it – and cancer cells – work.
In most healthy cells with a good supply of oxygen, energy in the form of adenosine triphosphate (ATP) is generated through oxidative phosphorylation in the mitochondria. But, in the 1920s, a scientist called Otto Warburg discovered that cancer cells tend to favor glycolysis as a means of energy generation – a phenomenon that became known as the “Warburg effect”.
At first glance, it seems counterintuitive that they would do this – glycolysis produces a measly two ATP molecules for each glucose molecule compared with 36 via oxidative phosphorylation. However, it is thought that the adaptation confers a major advantage to proliferating cancer cells; it helps them to compete for fuel resources and they can also use the intermediate products to synthesis macromolecules needed for growth.
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This increase in metabolic activity can be witnessed by an increase in glucose consumption. Since the 1980s, it has been thought that the uptake of FDG – a radioactively labelled glucose analogue – closely correlates with total glucose consumption. Using positron emission tomography (PET), the level of uptake of the molecule can be observed – because FDG cannot participate in all of the reaction steps to produce ATP, it gets trapped and accumulates in the mitochondria. The level of this accumulation correlates with tumor aggressiveness and can be used in cancer staging, monitoring treatment responses and is frequently used as a proxy for drug response during clinical trials.
The use of FDG in this way has had a significant impact on shaping the use of PET as a major clinical tool in cancer. But new research using PET suggests that decades-held assumptions about cancer-cell metabolism that underpin the technique may not actually hold true. Far from being a cause for despair, though, the findings could lead to better diagnoses and new targeted treatments.
In a paper by Marini et al. (2016), a team of researchers outline how they had been studying the effects of metformin – a diabetes drug that inhibits oxidative phosphorylation – on cancer cells using FDG-PET. The researchers had assumed that the drug would lead to even greater use of glycolysis – that glucose consumption would go up and FDG uptake would increase. But they found an unexpected result – FDG uptake actually went down while glucose consumption, measured directly, went up. How could this be and what was going on?
The researchers found that the result hinged on a previously undiscovered pathway for glucose metabolism. In the presence of metformin, the processes in the mitochondria resulting in the uptake and accumulation of FDG weren't affected at all, and so were not uninvolved in explaining the relationship between glucose and FDG uptake. Instead, they found that FDG was preferentially accumulating in a different part of the cell – the endoplasmic reticulum.
Here, the researchers showed that FDG can interact with an enzyme called hexose-6-phosphate-dehydrogenase (H6PD) that is found attached to the inside of the endoplasmic reticulum and thereby the molecule accumulates within the endoplasmic reticulum. Metformin interferes with the catalytic activity of the H6PD, explaining why FDG uptake depletes when cancer cells are treated with the drug.
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The team found that this pathway is fueled by glucose and, when H6PD activity is selectively inhibited, glucose consumption significantly falls. Additionally, treatment with metformin and an H6PD-inihibitor both resulted in decreased proliferation rate and increased cell death.
As a result, the researchers suggest that FDG uptake, while still relating to cancer-cell proliferation, is less a surrogate for glycolysis rate, and more an indication of H6PD activity. The findings could lead to new targeted treatments and improved clinical cancer diagnoses, they say. And the research revealed that H6PD, which had been credited only with a function in steroid-hormone signaling pathways, has a much greater role than was previously known.
New standards in molecular imaging
For the in vitro aspects of their experiments, the researchers used a Bruker Albira preclinical PET system. The technology seamlessly integrates PET, SPECT and CT in one compact footprint, facilitating understanding of biological processes including gene expression, disease progression, enzyme activity and pharmacodynamics.
The latest model, the Albira Si, is the first commercially available SiPM-based PET with unparalleled precision and resolution in three dimensions.
- Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clinical Cancer Research 2005; 11: 2785-2808.
- Marini C, Ravera S, Buschiazzo A, et al. Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate. Scientific Reports 2016; 6: 25092. doi: 10.1038/srep25092.
- Vander Heiden MG, Cantley LC & Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029-1033.
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