Is There a Role for Carbohydrate Restriction in the Treatment and Prevention of Cancer?

Rainer J Klement; Ulrike Kämmerer


Nutr Metab. 2011;8(75) 

In This Article

Tumor Cell Metabolism - It's All About Glucose

That there exists an intimate connection between CHOs and cancer has been known since the seminal studies performed by different physiologists in the 1920s. Treating diabetic patients, A. Braunstein observed in 1921 that in those who developed cancer, glucose secretion in the urine disappeared. Further, culturing tissue of benign and malign origin in glucose-containing solutions, he quantified the much higher consumption by cancer tissue compared to muscle and liver.[33] One year later, R. Bierich described the remarkable accumulation of lactate in the micromilieu of tumor tissues[34] and demonstrated lactate to be essential for invasion of melanoma cells into the surrounding tissue.[35] The most accurate and well known experiments were published by Otto Warburg and colleagues from 1923 on.[36–38] Warburg observed that tumor tissue ex vivo would convert high amounts of glucose to lactate even in the presence of oxygen (aerobic glycolysis), a metabolic phenotype now referred to as the Warburg effect. This meant a sharp contrast to normal tissue which was known to exhibit the Pasteur effect, i.e., a decrease of glucose uptake and inhibition of lactate production under aerobic conditions. Today, the Warburg effect is an established hallmark of cancer, i.e., a pathological capability common to most, if not all, cancer cells.[39] At first sight, the reason why many cancers should run preferentially on glucose to produce energy seems counter-intuitive: basic biochemistry textbooks tell us that glycolysis partially oxidizes the carbon skeleton of one mole of glucose to two moles of pyruvate, yielding two moles of ATP and NADH. In normal cells under normoxic conditions, pyruvate is oxidized in the mitochondria by the enzyme pyruvate dehydrogenase, creating acetyl-CoA which is further utilized in the tricarboxylic acid cycle (TCA or Krebs cycle) to yield a total of 32+ moles of ATP. Thus, the oxidation of pyruvate in the mitochondria supplies 30+ additional moles of ATP compared to its reduction to lactate via lactate dehydrogenase A (LDHA), which happens in case of insufficient oxygen levels or - in case of cancer cells - due to the Warburg effect.

Possible Causes for the "Warburg Effect"

Over the past years, however, it has become increasingly clear that malignant cells compensate for this energy deficit by up-regulating the expression of key glycolytic enzymes as well as the glucose transporters GLUT1 and GLUT3, which have a high affinity for glucose and ensure high glycolytic flux even for low extracellular glucose concentrations. This characteristic is the basis for the wide-spread use of the functional imaging modality positron emission tomography (PET) with the glucose-analogue tracer 18F-fluoro-2-deoxyD-glucose (FDG) (Figure 1). There are mainly four possible drivers discussed in the literature that cause the metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer cells. The first one is mitochondrial damage or dysfunction,[40] which was already proposed by Warburg himself as the cause for tumorigenesis.[41] Somatic mutations in mitochondrial DNA (mtDNA) and certain OXPHOS genes can lead to increased production of reactive oxygen species (ROS) and accumulation of TCA cycle intermediates (succinate and fumarate) that trigger the stabilization of hypoxia inducible factor (HIF)-1α, inactivation of tumor suppressors including p53 and PTEN and upregulation of several oncogenes of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway.[42] In tumor cells, Akt plays a major role in resisting apoptosis and promoting proliferation, and it does so by reprogramming tumor cell metabolism.[43–45] Akt suppresses β-oxidation of fatty acids,[46] but enhances de novo lipid synthesis in the cytosol.[47,48] Akt also activates mTOR, a key regulator of cell growth and proliferation that integrates signaling from insulin and growth factors, amino acid availability, cellular energy status and oxygen levels.[49,50] In cancer cells, mTOR has been shown to induce aerobic glycolysis by up-regulating key glycolytic enzymes, in particular through its downstream effectors c-Myc and HIF-1α. Both of these transcription factors are involved in the expression of pyruvate kinase M2, a crucial glycolytic enzyme for rapidly proliferating cells.[51]

Figure 1.

PET image of a patient with a left central lung carcinoma (arrows). Note also the high FDG uptake by the kidneys (Fig D), brain and myocard (Figure E). Source: PET/CT Imaging Centre, University Hospital of Würzburg.

HIF-1α is further important for the adaption to hypoxia by increasing the expression of glycolytic enzymes including GLUT1 and hexokinase (HK)II as well as several angiogenic factors.[49,52] The observation that certain malignant cells are able to use both glycolysis and OXPHOS under aerobic conditions has been taken to argue that mitochondrial dysfunction alone is not a sufficient cause for the Warburg effect.[53] Indeed, somatic mutations in most oncogenes and tumor suppressor genes have been shown to directly or indirectly activate glycolysis even in the presence of oxygen. As described above, they do so mainly by hyperactivating major metabolic signaling pathways such as the insulin-like growth facor-1 receptor (IGFR1)-insulin receptor (IR)/PI3K/Akt/mTOR signaling pathway (Figure 2). In principle, hyperactivation of this pathway can occur at several points from alterations in either upstream (receptor) or downstream (transducer) proteins and/or disruption of negative feedback loops via loss-of-function mutations in suppressor genes.[44,45,54] Thus, genetic alterations in oncogenes and tumor suppressor genes are a second possible cause for the Warburg effect.

Figure 2.

The IGF1R-IR/PI3K/Akt/mTOR pathway and its manipulation through diet. Elevations in blood glucose concentrations lead to secretion of insulin with subsequent elevation of free IGF1. Binding of insulin and IGF1 to their receptor tyrosine kinases induces autophosphorylation of the latter which leads to subsequent activation of PI3K by one of at least three different pathways.[54] Further downstream, PI3K signaling causes phosphorylation and activation of the serine/threonine kinase Akt (also known as protein kinase B). Akt activates mammalian target of rapamycin (mTOR), which itself induces aerobic glycolysis by upregulating key glycolytic enzymes, in particular via its downstream effectors c-Myc and hypoxia inducible factor (HIF)-1α. mTOR is negatively affected through activation of AMPK, which can be achieved by dietary restriction.67 In addition, a possible negative interaction between insulin and AMPK is discussed in vivo.60

As a third mechanism, with advanced tumorigenesis, non-mutation induced stabilization of HIF-1α occurs through a lack of oxygen in hypoxic tumor regions and contributes to increased glycolysis. Proliferation of aggressive tumors proceeds too fast for concurrent vascularization, so that hypoxic regions will develop. Because the diffusion coefficients for glucose are larger than for oxygen, these regions rely heavily on glycolysis. Hypoxic cancer cells are particularly radio- and chemoresistant. In PET-studies, tumor areas with high FDG uptake have been consistently linked to poor prognosis[55,56] and are now being considered as important biological target volumes to receive dose escalations in radiation treatment.[57]

The Impact of Insulin and IGF1

Finally, chronic activation of the IGFR1-IR/PI3K/Akt survival pathway through high blood glucose, insulin and inflammatory cytokines has been proposed as a cause of carcinogenesis[30,58,59] and switch towards aerobic glycolysis. In this theory, hyperactivation of the IGFR1-IR signalling pathway does not occur primarily through somatic gene mutations, but rather through elevated concentrations of insulin and IGF1, allowing for more ligands binding to their receptors. Interestingly, gain-of-function mutations resulting in ligand-independent overactivation of both IGFR1 and IR are uncommon.[60] Furthermore, loss-of-function of the tumor suppressor PTEN may result in hypersensitivity to insulin/IGF1-mediated activation of the IGFR1-IR pathway rather than constitutive downstream activation.[60] Thus, it seems possible that high levels of insulin and IGF1 in the microenvironment favor cell survival and evolution towards malignancy instead of apoptosis in DNA-damaged cells. Indeed, both hyperglycemia and hyperinsulinemia are predictors of cancer occurrence and cancer-related mortality.[23,25,26] This highlights the link between the metabolic syndrome and cancer on the one hand and cancer and lifestyle factors like nutrition on the other. As indicated in Figure 2, restriction of dietary CHOs would counteract this signalling cascade by normalizing glucose and insulin levels in subjects with metabolic syndrome, in this way acting similar to calorie restriction/fasting.[61,62] Indeed, it has been shown in healthy subjects that CHO restriction induces hormonal and metabolic adaptions very similar to fasting.[63–66] Dietary restriction is able to inhibit mTOR signalling through a second, energy-sensing pathway by stimulating phosphorylation of AMP-activated protein kinase (AMPK).[67] In vitro, AMPK phosphorylation is sensitive to the ratio of AMP/ATP within the cell; in vivo, however, concentrations of glucose and other nutrients are kept fairly stable throughout calorie restriction, suggesting that hormones such as insulin and glucagon might play a more dominant role in regulating AMPK and thus mTOR activation.[60] This may open a second route to mimic the positive effects of calorie restriction through CHO restriction (Figure 2).

Glycolysis: Beneficial for Tumor Cells

Besides the ability to grow in hypoxic environments, a high glycolytic rate has several additional advantages for the malignant cell: First, it avoids the production of ROS through OXPHOS. Second, the phosphometabolites that accumulate during glycolysis can be processed in the pentose phosphate pathway for biosynthesis of nucleic acids and lipids. Similarly, overexpession of Akt induces an increased flow of pyruvate-derived citrate from the mitochondrion into the cytosol, where it is used for lipid biosynthesis. Third, a tumor cell focusing on glycolysis no longer relies on intact mitochondria and may evade apoptotic signalling which is linked to mitochondrial function. In addition, the genes and pathways that up-regulate glycolysis are themselves antiapoptotic.[40] Fourth, high glycolytic activity produces high levels of lactate and H+ ions which get transported outside the cell where they directly promote tumor aggressiveness[68] through invasion and metastasis, two other hallmarks of cancer. For this purpose, glycolytic tumor cells often show overexpression of monocarboxylate transporters (MCTs) and/or Na+/H+ exchangers[69] that allow them to effectively remove large amounts of H+ ions. For MDA-MB-231 breast cancer cells it has been shown that lactate drives migration by acting as a chemo-attractant and enhances the number of lung metastasis in athymic nude mice.[70] Lactate can also be taken up and used as a fuel by some malignant cells, and oxidative tumor cells have been shown to co-exist with glycolytic ones (both stromal and malignant) in a symbiotic fashion.[71] In glioma cells, lactate upregulates and activates the matrix metalloproteinase (MMP)- 2 which degrades the extra-cellular matrix and basement membrane.[72] Activation of MMPs may also occur in the microenvironment through low pH values in a similar way as discussed for carious decay of the dentin organic matrix through lactate released by cariogenic bacteria.[73] Acidification of the microenvironment further induces apoptosis in normal parenchymal and stromal cells[74,75] and therefore provides a strong selective growth advantage for tumor cells that are resistant to low pH-induced apoptosis.[76,77]


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