Article Figures & Data
Figures
- Figure 1
Fusion image of a radiotherapy planning CT and FDG-PET scan of a patient with a primary right-sided cT1 cN2b tonsillar squamous cell carcinoma after tonsillectomy. The high FDG uptake of the right lymph node conglomerates is indicative of highly glycolytic metastasis. Note, however, that FDG-PET only measures glucose uptake and conversion into glucose-6-phosphate, and can therefore not discriminate between lactate production or feeding of glycolysis intermediates and end products into the pentose phosphate pathway or citric acid cycle. The high lactate release which can be measured with other techniques such as magnetic resonance spectroscopy is, however, indicated for illustrative purposes since it is characteristic for aggressive metastasis.
- Figure 2
Putative effects of CHO restriction on normal and tumor tissue. During radiotherapy CHO restriction may induce a differential stress response between normal and tumor cells such that the former experience protection from and the latter sensitization to ionizing radiation. Additionally, through the elevation of ketone bodies and fatty acids, CHO restriction helps to conserve muscle tissue.
- Figure 3
Flow chart showing the proposed implementation of a low CHO diet for the HNC patient. The pictures show foods compatible with a ketogenic diet that have a creamy texture and thus are easy to swallow.
Tables
Gene Frequency (%)45 Implications for metabolism Loss of function mutations/deletions TP53 50-80 Loss of p53 leads to nuclear and mitochondrial DNA instability, increased oxidative stress, decrease of OXPHOS and up-regulation of glycolysis (reviewed in46,47) NOTCH1 14-15 Hypoactive Notch diminishes p53 levels and attenuates mitochondrial function, causing a switch to glycolysis and dependence on glucose48 PTEN 7 PTEN counteracts glycolysis by reversing the PI3K-mediated conversion of phosphatidylinositol1,4-biphosphate (PIP2) to phosphatidylinositol1,4,5-triphosphate (PIP3) that is required to activate Akt-mTOR signaling. Loss of PTEN therefore increases Akt activation. PTEN also counteracts glutaminolysis by reducing glutaminase levels through a PI3K-independent pathway49 Gain of function mutations/amplifications PIK3CA 6-20 PIK3CA encodes p110α, an isoform of the 110-kDa catalytic subunit of the class 1A phosphatidylinositol-3-kinase (PI3K). The PI3K-Akt-mTOR pathway is one of the most frequently hyperactivated signaling cascades in tumor cells. Enhanced Akt signaling induces a Warburg phenotype and increases the coupling of glycolysis to the mitochondrial citric acid cycle which yields intermediates for biosynthetic pathways and NADH as the primary electron donor for OXPHOS (reviewed in50) HRAS 4-5 HRAS encodes the small GTPase H-Ras, a member of the Ras superfamily of enzymes that become active when bound to GTP. Besides other pathways important for cell survival and proliferation, Ras-GTP directly acivates PI3K p110. Oncogenic H-Ras activation diminishes mitochondrial respiration, rendering transformed cells depend on glucose to fuel glycolysis51 Factors promoting glycolysis CHO restriction as a metabolic strategy to target these factors High blood glucose levels (Up-regulation of glycolytic enzymes) Blood glucose ↓, fatty acids ↑ (Fatty acids inhibit key glycolytic enzymes) Hypoxia Blood glucose ↓, ketones ↑ (Poor nutrient supply to hypoxic cells; hypoxic cells unable to efficiently oxidize ketones) Oncogenic signaling (Insulin/IGF-1-PI3K-Akt-mTOR) Blood glucose ↓, insulin ↓ (Counteracts PI3K pathway; also activates AMPK, inhibiting mTOR) Ketones ↑ (Class I and II HDAC inhibitors) Inflammation (High blood glucose levels and ROS promote inflammatory cytokine release) Blood glucose ↓ (Decreases ROS and inflammation)
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- Article
- Abstract
- Introduction
- The sweet tooth of HNCs
- Genetic and epigenetic alterations promote aerobic glycolysis
- Vulnerability of HNC cells to CHO restriction
- CHO restriction during radiation treatment
- CHO restriction to positively influence body composition
- Discussion: is CHO restriction in HNC patients realistic?
- Acknowledgements
- Footnotes
- References
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