The chapter discusses the intricate links between metabolism and cancer, highlighting how metabolic processes contribute to oncogenic mutations and altered cellular functions. Key points include: 1. **Metabolism and Oncogenic Mutations**: Metabolism generates oxygen radicals, which can cause oncogenic mutations. Activated oncogenes and loss of tumor suppressors alter metabolism, leading to aerobic glycolysis (the Warburg effect), where cells convert glucose to lactate despite the presence of oxygen. 2. **Cellular Metabolism and Growth**: Glucose and glutamine are crucial for cell growth and proliferation, providing carbon skeletons, NADPH, and ATP. Glucose is converted to pyruvate, which can enter the TCA cycle or be shunted to lactate under hypoxic conditions. Glutamine, a major bioenergetic substrate, contributes to the TCA cycle and lipid synthesis. 3. **Oxygen Radicals and Stress**: Reactive oxygen species (ROS) produced during metabolism can damage cellular components and alter cellular functions. They are regulated by antioxidants like glutathione and peroxiredoxins, and can influence cellular responses to metabolic stresses. 4. **Nutrient Sensing and Signaling**: Nutrient deprivation triggers the activation of AMPK, which enhances energy production and reduces biosynthetic processes. In contrast, nutrient availability activates mTOR, promoting cell growth and proliferation. 5. **Growth Factor-Stimulated Transcriptional Responses**: Growth factors like IGF-1 and EGF stimulate transcriptional programs that activate metabolic genes, including those involved in glycolysis, glutaminolysis, and fatty acid synthesis. Myc, a key oncogene, regulates these processes and is essential for cell growth and proliferation. 6. **Cancer and Animal Body Size**: The incidence of cancer is lower in large animals like elephants and whales, possibly due to lower metabolic rates and reduced oxidative stress. Caloric restriction in animals can reduce cancer risk by limiting cell division and reducing mutagenesis. 7. **Oncogenes and Tumor Suppressors**: Mutations in metabolic enzymes and oncogenes like Myc, Ras, and PI3K can directly alter metabolism and promote tumorigenesis. Tumor suppressors like p53 and PTEN also regulate metabolic processes. 8. **Tumor Microenvironment**: The metabolic profile of cancer cells is influenced by the tumor microenvironment, including hypoxia and nutrient limitations. Hypoxic cells can convert glucose to lactate, which is then used by aerobic cells. 9. **Therapeutic Opportunities**: Targeting altered metabolism in cancer cells offers potential therapeutic strategies. Inhibitors of metabolic enzymes like LDHA and glutaminase have shown preclinical anti-tumor effects. Understanding the metabolic similarities between normal and cancer cells may provide new avenues for immunotherapy and targeted therapies. Overall, the chapter emphasizes the complex interplay between metabolism and cancer, highlighting the potential for therapeutic interventions targeting metabolic pathways in cancer cellsThe chapter discusses the intricate links between metabolism and cancer, highlighting how metabolic processes contribute to oncogenic mutations and altered cellular functions. Key points include: 1. **Metabolism and Oncogenic Mutations**: Metabolism generates oxygen radicals, which can cause oncogenic mutations. Activated oncogenes and loss of tumor suppressors alter metabolism, leading to aerobic glycolysis (the Warburg effect), where cells convert glucose to lactate despite the presence of oxygen. 2. **Cellular Metabolism and Growth**: Glucose and glutamine are crucial for cell growth and proliferation, providing carbon skeletons, NADPH, and ATP. Glucose is converted to pyruvate, which can enter the TCA cycle or be shunted to lactate under hypoxic conditions. Glutamine, a major bioenergetic substrate, contributes to the TCA cycle and lipid synthesis. 3. **Oxygen Radicals and Stress**: Reactive oxygen species (ROS) produced during metabolism can damage cellular components and alter cellular functions. They are regulated by antioxidants like glutathione and peroxiredoxins, and can influence cellular responses to metabolic stresses. 4. **Nutrient Sensing and Signaling**: Nutrient deprivation triggers the activation of AMPK, which enhances energy production and reduces biosynthetic processes. In contrast, nutrient availability activates mTOR, promoting cell growth and proliferation. 5. **Growth Factor-Stimulated Transcriptional Responses**: Growth factors like IGF-1 and EGF stimulate transcriptional programs that activate metabolic genes, including those involved in glycolysis, glutaminolysis, and fatty acid synthesis. Myc, a key oncogene, regulates these processes and is essential for cell growth and proliferation. 6. **Cancer and Animal Body Size**: The incidence of cancer is lower in large animals like elephants and whales, possibly due to lower metabolic rates and reduced oxidative stress. Caloric restriction in animals can reduce cancer risk by limiting cell division and reducing mutagenesis. 7. **Oncogenes and Tumor Suppressors**: Mutations in metabolic enzymes and oncogenes like Myc, Ras, and PI3K can directly alter metabolism and promote tumorigenesis. Tumor suppressors like p53 and PTEN also regulate metabolic processes. 8. **Tumor Microenvironment**: The metabolic profile of cancer cells is influenced by the tumor microenvironment, including hypoxia and nutrient limitations. Hypoxic cells can convert glucose to lactate, which is then used by aerobic cells. 9. **Therapeutic Opportunities**: Targeting altered metabolism in cancer cells offers potential therapeutic strategies. Inhibitors of metabolic enzymes like LDHA and glutaminase have shown preclinical anti-tumor effects. Understanding the metabolic similarities between normal and cancer cells may provide new avenues for immunotherapy and targeted therapies. Overall, the chapter emphasizes the complex interplay between metabolism and cancer, highlighting the potential for therapeutic interventions targeting metabolic pathways in cancer cells