دانلود کتاب Tumor Angiogenesis. A Key Target for Cancer Therapy

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Foreword Acknowledgments Contents About the Editor Contributors Part I: Mechanisms of Tumor Angiogenesis Mechanisms of Tumor Angiogenesis Introduction Molecular Mechanisms of Angiogenesis Mechanisms Involved in Blood Vessel Formation Vasculogenesis Sprouting Angiogenesis Alternative Ways of Blood Supply in Tumors Intussusception Vasculogenic Mimicry Biological Processes Involved in Angiogenesis Sprouting of Blood Vessels and Endothelial Cell Proliferation Cues that Guide Vessel Navigation Vessel Remodeling, Stabilization, and Maturation Regression of Blood Vessels and Endogenous Inhibitors of Angiogenesis The Angiogenic Switch in Tumorigenesis Hypoxia and Tumor Angiogenesis Differences between Physiological and Tumor Neovascularization Differences between Normal and Tumor Vessels Conclusion Cross-References References The Role of VEGF in Controlling Vascular Permeability Introduction Vascular Endothelial Growth Factors (VEGFs) and Their Receptors Features Regulating Vessel Integrity Basal Permeability Endothelial Fenestrations The Glycocalyx The Blood-Brain Barrier (BBB) The Vesiculo-Vacuolar Organelle (VVO) Endothelial Junctions in Lymphatic and Blood Vessels Blood Flow Regulation: Implication for Basal Sieving VEGF-Induced Transient Vessel Leakage Leakage of Molecules Leakage of Cells Vascular Leakage in Disease Vascular Leakage and Cancer Vascular Leakage and Myocardial Pathology Vascular Leakage in Ocular Diseases Lymphatic Neoangiogenesis and Cancer Imaging Vascular Flow and Integrity Perspectives Acknowledgments Cross-References References Benefits and Pitfalls of Tumor Vessel Normalization Introduction Lessons and Questions from Anti-VEGF-A/VEGFR2 Therapy Hallmarks of Tumor Vessel Normalization Inducing Tumor Vessel Normalization Benefits of Tumor Vessel Normalization Pitfalls of Tumor Vessel Normalization Translational Implications Challenges for Clinical Application Summary Cross-References References The Impact of Endothelial Transcription Factors in Sprouting Angiogenesis Introduction Pro-angiogenic Transcription Factors The ETS Family of Transcription Factors: Essential for Endothelial Cell Development The cAMP Response Element-Binding Transcription Factors The GATA Family: Highly Expressed in Endothelial Cells Hypoxia-Inducible Factors (HIFs) The Transcriptional Regulation by YAP/TAZ MYC The Nuclear Factor (NF) κB Anti-angiogenic or Endothelial Quiescence-Promoting Transcription Factors The Forkhead Transcription Factors The Kruppel-Like Factors 2 and 4 The Nuclear Factor-Erythroid 2 p45-Related Factor (NRF2) The p53 Transcription Factor The Recombining Binding Protein Suppressor of Hairless (RBPJ) Conclusions and Future Directions References Endothelial Cell-Cell Junctions in Tumor Angiogenesis Introduction Molecular Basis of Tumor Angiogenesis Formation of the Vascular Network During Development Overview on Tumor-Induced Angiogenesis Vascular Leakage in Tumor Angiogenesis Endothelial Cell-Cell Junctions The Endothelial Tight Junctions The Endothelial Adherens Junctions VE-Cadherin in the Endothelial Barrier Endothelial Junctions in Tumor-Induced Angiogenesis Dynamics of Endothelial Junctions in Migration and Sprouting Endothelial Cell-Cell Junctions in Polarity Remodeling of Endothelial Junctions in Tumor Vascular Permeability Involvement of Endothelial Junctions in Tumor Vascular Aberrations Future Directions Cross-References References Controlling Vascular Permeability: How Does It Work and What Is the Impact on Normal and Pathological Angiogenesis Introduction Molecular Mechanism of Vascular Permeability Transcellular Permeability Paracellular Junctions/Permeability Vascular Permeability in Health and Disease Regulation of Vascular Permeability Inflammatory Cytokines The Impact of Vascular Permeability on Physiological and Pathological Angiogenesis Molecular Mechanism of Physiological Angiogenesis The Role of the Vascular Endothelial Growth Factor (VEGF) Anti-angiogenic Therapy in Cancer via Suppression of the VEGF-VEGFR System Summary Cross-References References Part II: Mechanisms of Tumor Lymphangiogenesis Angiopoietins and TIE Receptors in Lymphangiogenesis and Tumor Metastasis Introduction Comparison of Developmental and Tumor Lymphangiogenesis Origin of Lymphatic Endothelial Cells in Development Versus Tumor Functional Comparison of Lymphatic Network in Embryos and Tumor Angiopoietins and TIE Receptors in Developmental Lymphatic Remodeling and Maturation Angiopoietins in Developmental Lymphangiogenesis TIE Receptors in Lymphatic Network Formation TIE1 as a Critical Regulator of Collecting Lymphatic Vessels TIE2 in Lymphatic Versus Blood Vessel Formation Regulation of Lymphatic Remodeling and Maturation Lymphatic Endothelial Cell Junctions in Initial and Collecting Vessels Lymphatic Valve Morphogenesis SMC Coverage with Collecting Lymphatics ANGPT-TIE Pathway in the Modulation of Tumor-Associated Lymphangiogenic Microenvironment Angiopoietins in Tumor Lymphangiogenesis and Lymphatic Metastasis Lymphatic Regulator-Mediated Modulation of Tumor Immune Response Summary Cross-References References Significance and Molecular Regulation of Lymphangiogenesis in Cancer Introduction Normal Lymphatic Structure, Function, and Molecular Regulation Functions of the Lymphatic Vasculature Structural Features of the Lymphatic System Molecular Regulation of Lymphangiogenesis: VEGF-C and VEGF-D Embryonic Lymphangiogenesis Other Regulators of Lymphangiogenesis Tumor Lymphangiogenesis and Lymphatic Metastasis Tumor Lymphangiogenesis Lymphogenous and Hematogenous Pathways of Tumor Metastasis Mechanisms of Lymph Node Metastasis Lymphangiogenesis in the Lymph Nodes Lymph Node Metastasis Is an Important Prognostic Indicator Historical Perspective on Lymph Node Metastasis Lymph Node Metastasis as a Source of Distant Metastases Lymphangiogenesis in Target Organs for Metastasis Clinical Implications of Lymphangiogenesis Prognostic Significance of Lymphangiogenesis in Human Tumors Therapeutic Targeting of Lymphangiogenesis Conclusions Cross-References References Part III: Mechanisms of Anti-angiogenic Therapy Mechanisms of Anti-angiogenic Therapy Introduction Inhibition of Angiogenic Signaling Vascular Endothelial Growth Factor Inhibitors Tyrosine Kinase Inhibitors Inhibition of Vascular Progenitor Cells EPCs in Tumor Angiogenesis EPCs and Tumor Microenvironment Therapeutic Strategies EPCs in Cancer Diagnosis and Prognosis EPCs in Anti-Angiogenic Treatments Inhibition of Extracellular Matrix Remodeling Extracellular Matrix in Angiogenesis Composition and Structural Organization of Vascular Extracellular Matrix Cell Adhesion Receptors Integrins Other Receptors Targeting Angiogenic Microenvironment Inhibition of the Extracellular Matrix Inhibition of Integrins Regression of Tumor Blood Vessels Vascular-Disrupting Agents VDA Concept History of VDAs Types of Vascular-Disrupting Agents Flavonoids Tubulin Binding Agents Therapeutic Approaches of VDAs VDAs as Monotherapy Resistance to VDA Treatments VDAs in Combination Therapy Normalization of Tumor Vasculature and Microenvironment Abnormalities of Tumor Vessels Structural Abnormalities Functional Abnormalities Tumor Vessel Normalization Normalization of Endothelial Cells Normalization of Vessel Microenvironment Therapeutic Implications of Vascular Normalization Conclusion Cross-References References Part IV: Anti-angiogenic Targets The Role of the VEGF Signaling Pathway in Tumor Angiogenesis Introduction and Historical Note Identification of VEGF and Early Studies VEGF Receptors VEGF as a Therapeutic Target in Oncology FDA Approval of Bevacizumab in Metastatic Colorectal Cancer: The First FDA Approval for Anti-angiogenic Therapy in Cancer Small Molecule VEGFR TKIs Protein Inhibitors Targeting VEGF in Combination with Other Angiogenic Inhibitors Targeting VEGF in Combination with Immunotherapy Conclusions and Perspectives Cross-References References Anti-angiogenic Targets: Angiopoietin and Angiopoietin Receptors Introduction Angiopoietin Growth Factors and TIE RTKs Angiopoietins TIE Receptor Signaling Phenotypes of Mice with Genetic Deletions of the Angiopoietin-TIE Pathway ANGPT1 ANGPT2 TIE1 and TIE2 Angiopoietins in Inflammation and Vascular Remodeling Angiopoietins in Experimental Tumor Models Angiopoietins in Tumor Growth and Angiogenesis Combined Therapy of ANGPT2 and VEGF or Immune Checkpoint Inhibition Angiopoietins in Metastasis Additional Angiopoietin - TIE Associated Signaling Pathways and Their Potential as Therapeutic Targets VE-PTP Integrins TIE2-expressing Macrophages ANGPT2 - an agonist or an antagonist? Angiopoietins in Human Cancer Summary Cross-References References Part V: Pathology of Tumor Angiogenesis Pathology of Tumor Angiogenesis Introduction Scientific Perception (a) Historical Overview (b) Embryological Process for Vessel Development: Vascular Genesis and Angiogenesis (c) Vessel Formation Modes Further Angiogenic Mechanisms (d) Effects of Malignant Tumors and Precursor Lesions onto Angiogenesis (e) Histological Architecture (f) Signaling Molecules in Angiogenesis (g) Haemangiogenesis Carcinomatosa and Metastases (h) Malignant Tumor Tissue Breast Cancer Colorectal Cancer Future Directions Cross-References References Part VI: Imaging of Tumor Angiogenesis Imaging Tumor Angiogenesis Introduction Imaging Angiogenesis: The Technologies Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) Methodological Considerations Biological Relevance of Imaging Techniques DCE-MRI Assessment of VEGF Inhibitors MRI Evaluation of Tumor Vasculature and Drug Development Mechanisms of Action and Imaging The Search for Predictive Biomarkers Proof of Principle Imaging Effects Are Necessary But Not Sufficient Why This Technology Remains Important Pharmacodynamic PET Scanning Studies of [18F]-FDG-PET Studies of [15O]-H2O and [18F]-FLT Emerging Imaging Technologies Future Directions Cross-References References Part VII: Biomarkers for Anti-angiogenic Therapy Biomarkers for Anti-angiogenic Therapy Introduction Tissue-Based Biomarkers Biomarkers of Pro-angiogenic Pathway Activation Microenvironmental Biomarkers Metabolic Biomarkers Blood-Based Biomarkers Cytokines and Pro-angiogenic Factors Circulating Endothelial and Endothelial Progenitor Cells Circulating Tumor Cells Neutrophil-to-Lymphocyte Ratio Genetics and Epigenetics Genetic Alterations Single-Nucleotide Polymorphisms (SNPs) DNA Hypermethylation MicroRNAs Drug Toxicities as Biomarkers of Drug Efficacy Hypertension and Anti-angiogenic Therapy Skin Toxicity and Anti-angiogenic Therapy Imaging-Based Biomarkers Conclusion Cross-References References Part VIII: Mechanisms of Resistance in Anti-angiogenic Therapy Anti-angiogenic Cancer Therapy: Development of Resistance Introduction Anti-angiogenesis Development of Resistance Normalization of Tumor Blood Vessels and Pericyte Coverage Hypoxia Recruitment of Inflammatory Cells and Immature Myeloid Cells Alternative Mechanisms of Tumor Vessel Formation Genomic Instability of Tumor Endothelial Cells and Increase of Metastatic Potential Conclusion Cross-References References Part IX: Mechanisms of Synergy in Combinations of Anti-angiogenics and Other Targeted Therapies Cytotoxics and Anti-angiogenics: Metronomic Therapies Introduction The Combination of Cytotoxic Drugs and Anti-Angiogenic Compounds Metronomic Chemotherapy Resistance to Metronomic Chemotherapy Future Directions Cross-References References Anti-angiogenics and Radiation Therapy Introduction Rationale for Combination of Radiotherapy with Anti-angiogenic Therapy Effects of Radiation on Angiogenesis Preclinical Evidence of Combined Anti-angiogenesis and Radiotherapy Clinical Experience Clinical Efficacy of Anti-angiogenic Therapy in Combination with Radiotherapy Toxicity Profile Summary Cross-References References Combination of Anti-angiogenics and Other Targeted Therapies Introduction Synergy Between Anti-angiogenic Therapies and EGFR Inhibition Combining Bevacizumab (VEGF) and Cetuximab (EGFR) Combining Bevacizumab (VEGF) and Panitumumab (EGFR) Combining Bevacizumab (VEGF) and Erlotinib (EGFR) Combining Bevacizumab (VEGF) and HER2-Directed Therapy Tyrosine Kinase Inhibitors Blocking Both VEGFR and EGFR Synergy Between Anti-angiogenics and Immune Cell Therapies Combining VEGF and CTLA4 Blockade Combining VEGF and PDL1/PD1 Blockade Synergy Between VEGF Blockade and Temsirolimus Synergy of Three Targeted Agents Including VEGF Blockade Combined Blockade of VEGF and Ang2 Signaling: Humanized Tri-specific Nanobody A Novel VEGFR2 Targeted Antibody-Based Fusion Protein (mAb04-MICA) Conclusion Cross-References References Part X: Anti-angiogenics in Gastrointestinal Cancers Anti-angiogenic Targeting in Metastatic Colorectal Cancer Therapy Introduction Colorectal Cancer The Role of Tumor Angiogenesis in Colorectal Cancer Anti-angiogenic Treatment Approved Monoclonal Antibodies and Derived Constructs Bevacizumab First-Line Treatment Chemotherapy Doublets ± Bevacizumab 5-FU-Based Chemotherapy ± Bevacizumab Chemotherapy Triplet ± Bevacizumab Second-Line Therapy Maintenance Therapy Bevacizumab Treatment Beyond Progression Aflibercept Ramucirumab Approved Tyrosine Kinase Inhibitor Regorafenib Anti-angiogenic Drugs in Development in mCRC Fruquintinib Nintedanib Famitinib Brivanib Cediranib Lenvatinib Linifanib Motesanib Tivozanib Trebananib Vandetanib Vatalanib Additional New Anti-angiogenic Agents in Early Clinical Development Summary Cross-References References Anti-angiogenics in Gastroesophageal Cancer Introduction The Role of Angiogenesis in Gastroesophageal Cancer Biological Background Key Angiogenic Pathways in Gastric Cancer Vascular Endothelial Growth Factor (VEGF) Platelet-Derived Growth Factor (PDGF) Angiopoietin: Tie2 Integrins Cellular Components of the Tumor Stroma that Drive Angiogenesis in Gastric Cancer Potential Novel Targets and Drug Development Angiogenesis-Related Biomarker Research and Gastric Cancer Clinical Results on Angiogenesis Inhibitors in Gastroesophageal Cancer Antibodies Targeting VEGF with Bevacizumab Targeting VEGF-R2 with Ramucirumab Tyrosine Kinase Inhibitors Sunitinib Sorafenib Regorafenib Apatinib Future Directions Cross-References References Anti-angiogenics in Pancreatic Cancer Therapy Introduction Pathogenesis Experimental and Clinical Diagnostic Modalities for Angiogenesis in PDAC and pNET Tumorigenesis and Angiogenesis in Pancreatic Adenocarcinoma Pathophysiology Experimental Studies Tumorigenesis and Angiogenesis in pNET Pathophysiology Experimental Studies Clinical Studies PDAC Vaccination Studies Interferon Alpha Antibodies and Targeted Proteins Kinase Inhibitors PNET Kinase Inhibitors Future Directions Cross-References References Anti-angiogenics in Hepatocellular Cancer Therapy Introduction Inhibition of Angiogenesis in HCC Inhibition of Angiogenesis with Transarterial Chemoembolization Inhibition of Angiogenesis with Systemic Therapy Sorafenib Sunitinib Brivanib Linifanib Cabozantinib and Tivantinib Regorafenib Bevacizumab Ramucirumab Combination of Local and Systemic Therapy TACE in Combination with Systemic Therapy Conclusion References Part XI: Anti-angiogenics in GIST Inhibition of Tumor Angiogenesis in GIST Therapy Introduction Angiogenesis GIST Anti-angiogenic Therapy of GIST Imatinib Sunitinib Regorafenib Other Anti-angiogenic Inhibitors Tumor Response Evaluation in the TKI Era The Other Side of the Coin: Mechanism of Acquired Resistance and Toxicity Conclusion Cross-References References Part XII: Anti-angiogenics in Other Soft Tissue Sarcomas The Value of Anti-angiogenics in Soft Tissue Sarcoma Therapy Introduction Angiogenesis and Sarcoma Preclinical Data Anti-angiogenic Agents Systemic Chemotherapy Future Directions Conclusion Cross-References References Part XIII: Anti-angiogenics in Head and Neck Cancer The Value of Anti-angiogenics in Head and Neck Cancer Therapy Introduction Targeting Angiogenesis in Head and Neck Squamous Cell Carcinoma Monoclonal Antibody Inhibiting VEGF: Bevacizumab Bevacizumab for the Treatment of Locally Advanced HNSCC Combining Bevacizumab with Cisplatin and Radiation Therapy Combining Bevacizumab with Radiation Therapy and Other Chemotherapeutic Regimens Combining Bevacizumab with Radiation Therapy and Both Chemotherapy and Anti-EGFR Therapy Bevacizumab for the Treatment of Recurrent and Metastatic HNSCC Combining Bevacizumab with Anti-EGFR Therapies Combining Bevacizumab with Anti-EGFR Therapies and mTOR Inhibitors Combining Bevacizumab with Chemotherapy Tyrosine Kinase Inhibitors Sorafenib Single-Agent Sorafenib in the Setting of Recurrent and/or Metastatic HNSCC Sorafenib in Combination with Chemotherapy in the Setting of Recurrent and/or Metastatic HNSCC Sorafenib in Combination with Anti-EGFR Therapies in the Setting of Recurrent and/or Metastatic HNSCC Sorafenib in the Setting of Locally Advanced Disease Sunitinib Sunitinib in the Setting of Recurrent and/or Metastatic HNSCC Sunitinib in the Setting of Locally Advanced HNSCC Novel TKI Under Study Vandetanib Pazopanib Axitinib Mechanisms of Resistance to VEGF-/VEGFR-Targeted Therapy Conclusion Cross-References References Part XIV: Anti-angiogenics in Lung Cancer Inhibition of Tumor Angiogenesis in the Treatment of Lung Cancer Introduction Bevacizumab in Addition to First-Line Chemotherapy of Advanced NSCLC Bevacizumab in the Treatment of Epidermal Growth Factor Receptor Mutation Positive Cases Other Anti-angiogenic Drugs Tested as First-Line Treatment of Advanced NSCLC Anti-angiogenic Drugs in the Second-Line Treatment of Advanced NSCLC The Attempt of Targeting Angiogenesis in the Adjuvant Treatment of NSCLC Anti-angiogenic Drugs in the Treatment of Small Cell Lung Cancer Bevacizumab as Part of First-Line Treatment of Malignant Pleural Mesothelioma Conclusion Cross-References References Part XV: Anti-angiogenics in Gynecological Tumors The Value of Anti-angiogenics in Breast Cancer Therapy Introduction Clinical Relevance of Anti-angiogenics in Metastatic Breast Cancer Bevacizumab Sorafenib Sunitinib Metronomic Chemotherapy Clinical Relevance of Anti-angiogenics in Nonmetastatic Breast Cancer Bevacizumab Sorafenib Predictive Factors for Treatment Efficacy of Angiogenesis Inhibitors Conclusion Cross-References References The Value of Anti-angiogenics in Ovarian Cancer Therapy Introduction Anti-angiogenic Treatment with Bevacizumab Bevacizumab in First-Line Therapy Bevacizumab in Recurrent, Platinum-Sensitive Ovarian Cancer Bevacizumab in Recurrent, Platinum-Resistant Ovarian Cancer Inhibition of Angiogenesis by Multi-kinase Inhibitors Pazopanib Nintedanib Sorafenib Cediranib Sunitinib Other Anti-angiogenic Treatment Strategies Trebananib Future Directions Additional Combination Partners: PARP Inhibitors Additional Combination Partners: Immunotherapies Conclusion Cross-References References The Value of Anti-angiogenics in Cervical Cancer Therapy Introduction Screening for Cervical Cancer Preinvasive Changes Risk Factors for Cervical Cancer Treatment Options Angiogenesis in Cervical Cancer Clinical Relevance of Anti-angiogenics in Cervical Cancer Bevacizumab (Avastin) Other Anti-angiogenic Drugs Future Directions VEGF-Pathway Other Angiogenic and Non-angiogenic Mechanisms Conclusion Cross-References References Part XVI: Anti-angiogenics in Urological Tumor Therapy Anti-angiogenics in Kidney Cancer Therapy Introduction Angiogenesis and Anti-angiogenics TKI (Tyrosine Kinase Inhibitors) Side Effects of Tyrosine Kinase Inhibitors (TKI) Bevacizumab plus Interferon (IFN)-α mTOR Inhibitors Immunotherapy Chemotherapy Future Directions References The Value of Anti-angiogenics in Prostate Cancer Therapy Introduction The Biology of Prostate Cancer Neo-angiogenesis Proangiogenic Factors Vascular Endothelial Growth Factors (VEGFs) Platelet-Derived Growth Factors (PDGFs) Fibroblast-Derived Growth Factors (FGFs) Angiopoietins (Angs) Anti-angiogenic Factors Mechanisms of Resistance to Angiogenesis Inhibition Adaptive Resistance Innate Resistance Anti-angiogenic Therapies of Advanced Prostate Cancer Bevacizumab Aflibercept Tyrosine Kinase Inhibitors (TKIs): Sunitinib, Sorafenib, and Cabozantinib Tasquinimod Thalidomide Lenalidomide Conclusion Cross-References References The Value of Anti-angiogenics in Bladder Cancer Therapy Introduction Angiogenesis in Bladder Cancer: Microvessel Density and Other Early Approaches Angiogenic Pathways in Bladder Cancer Targeting Angiogenesis in Bladder Cancer Clinical Trials Bevacizumab Aflibercept Sunitinib Everolimus Sorafenib Pazopanib Cabozantinib Ramucirumab/Icrucumab Vandetanib Nintedanib/Regorafenib Conclusion Cross-References References Part XVII: Anti-angiogenics in Brain Tumors The Value of Anti-angiogenics in Primary Brain Tumor Therapy Introduction Glioblastoma Multiforme Diffuse Astrocytic and Oligodendroglial Tumors Meningioma Medulloblastoma Other Types of Brain Tumors Angiogenesis and Glioblastoma Angiogenesis and Astrocytic and Oligodendroglial Tumors Angiogenesis and Meningioma Angiogenesis and Medulloblastoma Anti-angiogenic Agents Mechanisms of Resistance Clinical Trials Newly Diagnosed Glioblastoma Recurrent Glioblastoma Bevacizumab beyond Progression Meningioma Clinical Implications of Bevacizumab Therapy in Glioblastoma Summary Conclusion Cross-References References Anti-angiogenics in Brain Metastases: Perspectives and Experiences Introduction Novel Concepts for Brain Metastases Prevention with Anti-angiogenics Therapy of Brain Metastases by Anti-angiogenics Palliative Benefits by Anti-angiogenics in Brain Metastases Pragmatic Use of Anti-angiogenics in Heavily Pretreated Patients Conclusions and Outlook Cross-References References Part XVIII: Anti-angiogenics in Multiple Myeloma The Value of Anti-angiogenics in Multiple Myeloma Therapy Introduction Multiple Myeloma and Angiogenesis Proangiogenic Environment Through Plasma Cell Proliferation, Angiogenic Cytokines, and Hypoxia Angiostatic Factors Vasculogenesis Exosomes and miRNA Relevance of the Bone Marrow Microenvironment for Myeloma Progression and Angiogenesis Biomarkers and Imaging of Angiogenesis in Multiple Myeloma Gene Expression Data Tissue-Derived Biomarkers Blood-Borne Factors Imaging Anti-angiogenic Strategies in Multiple Myeloma Anti-angiogenic Activity of Approved Drugs for Multiple Myeloma Immunomodulatory Drugs: Molecular Mechanisms of Action and Anti-angiogenic Activity Immunomodulatory Drugs: Clinical Application and Use Proteasome Inhibitors: Anti-angiogenic Activity and Clinical Use HDAC Inhibitors Clinical Trials with Anti-angiogenic Compounds Anti-VEGF Approach: Anti-VEGF Antibodies and Multi-targeting TKIs Targeting Hypoxia and HIF-1α Inhibition Inhibition of Heparanase and Heparin-Binding Growth Factors PI3 Kinase Inhibitors Future Directions Nanoparticles and Materials Development New Targets Cross-References References Part XIX: Anti-angiogenics in Human Metabolism The Implication of Anti-angiogenic Treatment of Malignancies on Human Metabolism Introduction Mechanisms of Resistance Hypoxia and Necrosis Hypoxia and Metabolism Hypoxia and Invasion Metabolic Adaptations to Anti-angiogenic Therapy Conclusion Cross-References References Index