Tumor Angiogenesis. A Key Target for Cancer Therapy

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