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Book Details
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Contents | xi | ||
| Preface | v | ||
| Chapter 1 Tumor Hypoxia and Radiotherapy | 1 | ||
| 1. Tumor Hypoxia and Radiation | 1 | ||
| 2. The Oxygen Effect: Timing, Mechanism, and Concentration \r | 2 | ||
| 3. Radioresistance of the Hypoxic Fraction: in vivo and Human Tumors\r | 9 | ||
| 4. Targeting Hypoxia to Overcome Radioresistance | 12 | ||
| 4.1. Methods to quantify tumor hypoxia | 12 | ||
| 4.2. Radiation fractionation: reoxygenation for tumor hypoxia | 14 | ||
| 4.3. Hypoxic cell radiosensitizers and cytotoxins | 17 | ||
| 4.4. Radiation dose boosting | 23 | ||
| 4.5. High-LET particle radiotherapy | 26 | ||
| 5. Predicting Radioresistance and Radiation Treatment Outcomes\r | 30 | ||
| 5.1. Predicting treatment response with imaging | 30 | ||
| 5.2. Modeling the effect of hypoxia | 31 | ||
| References | 34 | ||
| Chapter 2 Post-translational Modifications of the Hypoxia Inducible Factors | 49 | ||
| 1. Introduction | 49 | ||
| 1.1. HIF- s: A brief introduction\r | 50 | ||
| 1.1.1. HIF-1 \r | 50 | ||
| 1.1.2. HIF-2 \r | 51 | ||
| 1.1.3. HIF-3 \r | 51 | ||
| 2. Post-translational Modifications of HIF- s\r | 52 | ||
| 2.1. Hydroxylation of proline 402/564 | 52 | ||
| 2.1.1. Hydroxylation of asparagine by FIH-1 | 53 | ||
| 2.1.2. Polyubiquitination of HIF- by pVHL\r | 54 | ||
| 2.1.3. Acetylation of HIF- s\r | 54 | ||
| 2.1.4. Phosphorylation of HIF-1 by MAPK\r | 55 | ||
| 2.1.5. SUMOylation | 56 | ||
| 2.1.6. S-Nitrosylation | 56 | ||
| 3. Targeting Post-translational Modifications in Tumor Therapy | 57 | ||
| 3.1. Stabilization of HIF- through manipulatingits post-translational modifications for vascularand tissue regeneration\r | 58 | ||
| 4.1. Summary | 59 | ||
| References | 60 | ||
| Chapter 3 Hypoxia and Metastasis | 69 | ||
| 1. Introduction — Cancer Metastasis | 69 | ||
| 2. Hypoxia and the Tumor Microenvironment | 71 | ||
| 2.1. The extracellular matrix | 71 | ||
| 2.1.1. Integrins | 72 | ||
| 2.1.2. Matrix metalloproteinases | 73 | ||
| 2.1.3. Extrinsic factors | 74 | ||
| 2.2. Epithelial to mesenchymal transition | 76 | ||
| 3. Hypoxia and Circulating Tumor Cells | 77 | ||
| 3.1. Anoikis | 78 | ||
| 3.2. Shear forces | 79 | ||
| 3.3. The immune response | 80 | ||
| 4. Hypoxia and Distant Metastasis | 81 | ||
| 4.1. Homing of circulating tumor cells | 81 | ||
| 4.2. Mesenchymal to epithelial transition | 82 | ||
| 4.3. Tumor cell survival and growth | 83 | ||
| 4.4. Angiogenesis | 84 | ||
| 5. Targeting Hypoxia and Metastasis in the Clinic | 85 | ||
| 6. Conclusions | 90 | ||
| References | 90 | ||
| Chapter 4 Hypoxia and Cancer Stem Cell Regulation | 101 | ||
| 1. Introduction | 101 | ||
| 2. The Clonal versus Stem Cell Cancer Models | 102 | ||
| 3. The Stem Cell Niche | 104 | ||
| 4. Tissue Hypoxia | 105 | ||
| 4.1. Hypoxia inducible factors | 105 | ||
| 4.2. Oxygen-dependent regulation of the HIFs | 106 | ||
| 4.3. Oxygen-independent regulation of the HIFs | 108 | ||
| 4.4. HIFs and cancer aggressiveness | 109 | ||
| 5. Hypoxia Promotes Immature, Stem Cell-Like Phenotypes\r | 110 | ||
| 6. Pseudohypoxia | 110 | ||
| 6.1. The hypoxic and pseudohypoxic cancer stem cell niches\r | 114 | ||
| Acknowledgments | 116 | ||
| References | 116 | ||
| Chapter 5 Hypoxia and Senescence | 127 | ||
| 1. Introduction | 127 | ||
| 2. Phenotypes of Senescent Cells | 128 | ||
| 3. Markers of Senescent Cells | 129 | ||
| 4. Molecular Pathways Driving Senescence | 131 | ||
| 5. Stresses that Induce Senescence | 132 | ||
| 6. Senescent Cells and the Hypoxic Microenvironment | 136 | ||
| References | 140 | ||
| Chapter 6 Hypoxic Reprograming of Tumor Metabolism, Matching Environmental Supply with Biosynthetic Demand\r | 147 | ||
| 1. Introduction | 147 | ||
| 2. Genesis of Tumor Hypoxia | 148 | ||
| 3. Hypoxia-Inducible Factor (HIF) is a Key Regulator of Hypoxic Adaptation\r | 149 | ||
| 4. Reprogramming of Glucose Metabolism | 151 | ||
| 5. Pyruvate Metabolism in Hypoxia | 152 | ||
| 6. Regulation of Mitochondrial Biogenesis and Function in Hypoxia\r | 154 | ||
| 7. Reprogramming of Glutamine Metabolism | 155 | ||
| 8. Reprogramming of Glycogen Metabolism | 156 | ||
| 9. Lipid Metabolism and Storage in Hypoxia | 158 | ||
| 10. Hypoxia Induced miRNAs Add an Additional Layer to Regulate Metabolism\r | 159 | ||
| 11. Conclusions | 160 | ||
| References | 160 | ||
| Chapter 7 Regulation of DNA Repair by Hypoxia | 169 | ||
| 1. Introduction | 169 | ||
| 2. Hypoxia Induces Genetic Instability\r | 170 | ||
| 2.1. Increased DNA damage and mutations under hypoxia\r | 170 | ||
| 2.2. Impaired DNA repair under hypoxia | 172 | ||
| 3. Global Regulation of Epigenetic Pathways by Hypoxia\r | 174 | ||
| 3.1. Hypoxia-induced histone modifications | 174 | ||
| 3.2. Hypoxia-dependent regulation of genes involved in histone modifications\r | 175 | ||
| 3.3. DNA methylation regulated by hypoxia | 176 | ||
| 4. Hypoxia Drives Silencing of Specific DNA Repair Genes Through Epigenetic Regulation\r | 176 | ||
| 4.1. Hypoxia-induced epigenetic silencing of the BRCA1 promoter\r | 177 | ||
| 4.2. Hypoxia-induced epigenetic silencing of the promoters of mismatch repair genes\r | 178 | ||
| 4.3. LSD1 mediates in H3K4 demethy lationat the BRCA1 promoter induced by hypoxia\r | 180 | ||
| 4.4. LSD1 and PLU1 are required for hypoxia induced histone modifications at the MLH1 promoter\r | 181 | ||
| 5. Concluding Remarks and Future Perspectives | 181 | ||
| Acknowledgment | 182 | ||
| References | 182 | ||
| Chapter 8 Regulation of the Hypoxic Response by Non-coding RNAs\r | 189 | ||
| 1. Introduction | 190 | ||
| 2. Non-coding RNAs — Not “Junk” Any More | 191 | ||
| 3. Transfer RNA-Derived RNA Fragments (tRFs) | 193 | ||
| 4. lncRNAs | 193 | ||
| 4.1. H19 | 194 | ||
| 4.2. lincRNA-p21 | 194 | ||
| 4.3. lncRNA-LET | 195 | ||
| 4.4. Hypoxia-induced non-coding ultraconserved transcripts (HINCUTs)\r | 195 | ||
| 5. NATs | 196 | ||
| 6. miRNAs | 196 | ||
| 6.1. miRNAs that regulate HIF-1 | 198 | ||
| 6.2. miRNAs induced under hypoxia | 199 | ||
| 6.2.1. miR-210, a marker for tumor hypoxia | 199 | ||
| 6.2.2. miR-210 target identification | 200 | ||
| 6.2.3. miR-210 regulates DNA damage response | 202 | ||
| 6.2.4. miR-210 regulation of apoptosis | 202 | ||
| 6.2.5. miR-210 regulation of cell cycle | 203 | ||
| 6.2.6. miR-210 regulation of angiogenesis | 204 | ||
| 6.2.7. miR-210 regulates mitochondrial metabolism | 206 | ||
| 6.2.8. miR-210 as a potential cancer therapeutic target | 207 | ||
| 6.2.9. Circulating miR-210 as a promising biomarker for cancer diagnosis and prognosis\r | 208 | ||
| 7. Concluding Remarks | 209 | ||
| Acknowledgments | 210 | ||
| References | 210 | ||
| Chapter 9 Hypoxia-Induced Endoplasmic Reticulum Stress | 225 | ||
| 1. Introduction | 225 | ||
| 2. Function of ER | 226 | ||
| 3. ER Stress | 226 | ||
| 4. Unfolded Protein Response | 227 | ||
| 5. IRE1 Signaling | 227 | ||
| 6. PERK Signaling | 230 | ||
| 7. ATF6 Signaling | 231 | ||
| 8. Hypoxia and the UPR Pathway | 232 | ||
| 10. Therapeutic Targeting of the UPR in Disease | 237 | ||
| 11. Concluding Remarks | 240 | ||
| References | 240 | ||
| Chapter 10 The Hypoxic Tumor Microenvironment and the Anti-cancer Immune Response\r | 249 | ||
| 1. Introduction\r | 250 | ||
| 1.1. Oxygen dependent regulation of HIF-1 | 251 | ||
| 2. Neutrophils | 253 | ||
| 3. Myeloid-derived Suppressor Cells | 255 | ||
| 4. Macrophages | 257 | ||
| 4.1. Macrophage polarization | 258 | ||
| 4.2. Tumor associated macrophages | 260 | ||
| 5. Dendritic Cells | 261 | ||
| 6. T cells | 263 | ||
| 6.1. CD4+ T cell differentiation | 263 | ||
| 6.2. Regulatory T cells | 266 | ||
| 6.3. Dynamic regulation of T cells by hypoxia | 269 | ||
| 7. CD8+ T cells | 270 | ||
| 7.1. HIF-1 and CD8+ T cell metabolism | 271 | ||
| 8. B cells | 273 | ||
| 9. Summary and Discussion | 273 | ||
| 10. Therapeutic Implications | 274 | ||
| Acknowledgments | 277 | ||
| References | 277 | ||
| Index | 293 |