Complexity of metabolic cancer control

Keywords: :

• autophagy
• blood glucose
• glucose deprivation treatment
• glutamine
• highly glycolytic cancers
• metabolic cancer control
• metabolic hierarchy
• metabolically inflexible cancer cells
• reverse Warburg effect
• tumor stroma

We respond to a paper by Ko and colleagues (“Glutamine fuels a vicious cycle of autophagy...”).¹ They hypothesize that tumor stroma are the central fuel generators for cancer growth, the so-called “reverse Warburg effect.”¹ Irrespective of whether this mechanism or the extensively quoted “Warburg effect”² accounts for energy production and biosynthesis, we propose (based on recent findings) that all cancer cell metabolites are either glucose-dependent or glucose-derived. We ask whether metabolic cancer control may be simpler than expected.

Ko and colleagues show that neighboring cancer-associated fibroblasts are stimulated to convert to glycolytic metabolism through cancer cell-initiated oxidative stress. The fibroblasts thus become glucose dependent.^1,3,4 This is the reason why the FDG-PET image of fibroblasts may be even larger than that of the primary tumors.¹

The fibroblasts become autophagic and consequently produce lactate as a glycolytic end product, which synergistically fuels cancer cell growth.^1,3,4 Apart from lactate, cancer-associated fibroblasts also produce ketone bodies and glutamine as end products, which are also used as cancer fuels.¹

Fortuitously, it has also recently been shown that glucose deprivation leads to a marked reduction in glutamine uptake.⁵ Therefore, if cancer cells and fibroblasts can be deprived of glucose, the cancer cells will not only be less able to metabolize glutamine but will also be deprived of lactate (the main end product of aerobic glycolysis). Certain cancer cells may attempt to adopt fatty-acid and ketone body oxidation, but this is also a glucose-dependent process in cancer cells.⁶ Glucose thus appears at the top of cancer cell (and fibroblast) metabolic hierarchy.

Therefore, if highly glycolytic cancer and metastatic cells (and associated fibroblasts) are deprived of glucose, all the cancer’s metabolic fuels will be downregulated, and glutamine will not be effectively metabolized. With this insight, metabolic control of highly glycolytic cancers and metastases (HGCM) could potentially be simplified to primarily targeting glucose.

We are further aided by the fact that increased glucose consumption in HGCM renders metabolically inflexible cancer cells more vulnerable to inhibition of glycolysis than normal cells.^7-9 We could thus potentially exploit the superior metabolic position of glucose for HGCM control.¹⁰

In summary, recent research shows that metabolic control of cancer might be less complex than expected and that the “reverse Warburg effect” may be partially addressed by exploiting the superior metabolic position of BG.