Hypoxia in Cancer: Significance and Impact on Cancer Therapy

Preface
Acknowledgment
Contents
Editors and Contributors
1: Hypoxia and Its Biological Implications for Cancer Therapy
	1.1 Introduction
	1.2 Hypoxia in Breast and Other Cancers
		1.2.1 Breast Cancer
		1.2.2 Ovarian Cancer
		1.2.3 Cervical Cancer
		1.2.4 Prostate Cancer
	1.3 Hypoxia in the Regulation of Tumor Microenvironment
	1.4 Hypoxia in Cancer Metastasis
	1.5 Hypoxia in Tumor Angiogenesis
	1.6 Mechanism of Drug Resistance in Cancer in Response to Hypoxia
	1.7 Hypoxia and Cancer Therapy
	1.8 Conclusion
	References
2: Hypoxia´s Function in Cancer
	2.1 Introduction
	2.2 Importance of HIF in Cancer Therapy
	2.3 Hypoxia-Inducible Factor (HIF)
	2.4 Implications of HIF Activation in Tumors
		2.4.1 Tumor Angiogenesis
		2.4.2 Metabolic Derangement
		2.4.3 Tumor Immune Response
	2.5 Tumor Metastasis and Hypoxia
	2.6 Tumor Hypoxia and Chemoresistance
		2.6.1 Hypoxia and Drug Resistance
	2.7 Hypoxia and New Treatment Modalities
	2.8 Hypoxia-Activated Prodrugs
	2.9 HIF-1α Expression
	2.10 HIF-1 Transcription
	2.11 HIF-1 Target Gene Products
	2.12 Drugs Targeting Hypoxic Signaling Tyrosine Kinase Receptors, RAS-MAPK Pathway, and mTOR Pathway
	2.13 UPR Targets
	2.14 Conclusion and Future Aspects
	References
3: Role of Hypoxia and Reactive Oxygen Species in Cancer Biology
	3.1 Introduction
	3.2 Cancer
	3.3 Hypoxia
	3.4 Role of Hypoxia in Cancer
	3.5 Free Radicals
	3.6 Oxidative Stress
	3.7 Role of Reactive Oxygen Species in Cancer
		3.7.1 ROS as Tumor-Promoting Agent (Carcinogenic Role)
		3.7.2 ROS Role in Tumorigenesis
		3.7.3 ROS Role in Invasion and Metastasis
		3.7.4 ROS Role in Angiogenesis
		3.7.5 ROS as Tumor-Suppressing Agent (Cytotoxic Role)
		3.7.6 ROS Role in Cellular Apoptosis
	3.8 Conclusions
	References
4: Hypoxic Tumor Microenvironment: Driver for Cancer Progression
	4.1 Introduction
	4.2 Tumor Microenvironment
		4.2.1 Cellular Components
		4.2.2 Acellular Components
		4.2.3 Physical and Chemical Properties
			4.2.3.1 Acidosis or Extracellular pH
			4.2.3.2 Hypoxia
			4.2.3.3 Interstitial Fluid Pressure (IFP)
			4.2.3.4 Tumor Fibrosis
	4.3 Hypoxia
		4.3.1 HIF Pathway
		4.3.2 Hypoxia and Metabolism
		4.3.3 Hypoxia and Its Role in EMT and Metastasis
		4.3.4 Hypoxia and Angiogenesis
	4.4 Clinical Impact of Hypoxia in Cancer Progression
	4.5 Diagnosis of Tumor Hypoxia
		4.5.1 Invasive Direct Methods
		4.5.2 Noninvasive Direct Measurements
			4.5.2.1 Phosphorescence Quenching
			4.5.2.2 Electron Paramagnetic Resonance (EPR)
			4.5.2.3 Overhauser-Enhanced MRI (OMRI)
			4.5.2.4 Magnetic Resonance Imaging (MRI)
			4.5.2.5 Endogenous and Exogenous Markers
				4.5.2.5.1 Pimonidazole and Pentafluoropropyl (EF5)
				4.5.2.5.2 Hypoxic-Inducible Factor (HIF-1α)
				4.5.2.5.3 Glucose Transporter 1 (GLUT-1)
				4.5.2.5.4 Carbonic Anhydrase IX
				4.5.2.5.5 Osteopontin
	4.6 Current Cancer Therapies Targeting Hypoxic Tumor Microenvironment
		4.6.1 Enhancing Radiotherapy
		4.6.2 Enhancing Chemotherapy
		4.6.3 Hypoxia-Targeted Therapy
			4.6.3.1 Modifying Tumor Microenvironment by Increasing Oxygen Concentration in Tissues
			4.6.3.2 Nanoparticles Acting as Oxygen Carriers
			4.6.3.3 Decomposition of Substances to Generate Oxygen
			4.6.3.4 Using Hypoxia Prodrugs to Assist Treatment
			4.6.3.5 Bioreductive Drugs
			4.6.3.6 Gene Therapy
	4.7 Conclusion and Future Perspectives
	References
5: Hypoxia and Senescence: Role of Oxygen in Modulation of Tumor Suppression
	5.1 Introduction
	5.2 Fundamentals of Cellular Senescence
		5.2.1 Morphological Alterations of Cellular Senescence
		5.2.2 Senescence-Associated Metabolic Changes
		5.2.3 Senescence-Associated Mitochondrial Dysfunction
		5.2.4 Main Effectors of Senescence: DNA Damage Responders and Cell Cycle Regulators
		5.2.5 Senescence-Associated Epigenetic Regulations
		5.2.6 Senescence-Associated Changes in Cell Survival Pathways
		5.2.7 Senescence-Associated Secretory Phenotype
	5.3 Oncogene-Induced Senescence (OIS) and Tumor Suppression
		5.3.1 Mechanisms of OIS
		5.3.2 OIS and Tumor Suppression
	5.4 Intersection of Hypoxia and Senescence
		5.4.1 Impact of Hypoxia on Regulation of Cell Cycle
		5.4.2 Impact of Hypoxia in Metabolism
		5.4.3 Impact of Hypoxia in OIS
	5.5 Conclusions and Future Perspectives
	References
6: Hypoxia-Regulated Gene Expression and Metastasis
	6.1 Introduction
	6.2 Hypoxia-Inducible Factors
	6.3 Hypoxia-Induced Regulators of Metastasis
		6.3.1 Epithelial to Mesenchymal Transition
		6.3.2 Signal Mediators of Hypoxia-Regulated EMT
		6.3.3 Transcription Factors of Hypoxia-Induced EMT
		6.3.4 Hypoxia-Regulated Enzymes in Cancer Invasion and Metastasis
		6.3.5 Hypoxia-Regulated Chemokines in Cancer Invasion and Metastasis
		6.3.6 Hypoxia-Regulated Adhesion Molecules in Cancer Invasion and Metastasis
		6.3.7 Hypoxia-Regulated Other Players Associated with Cancer Metastasis
	6.4 Conclusion
	References
7: MicroRNA Signatures of Tumor Hypoxia
	7.1 Introduction
		7.1.1 MicroRNA Biogenesis
		7.1.2 Role of miRNA in Tumor Angiogenesis
	7.2 MicroRNAs
		7.2.1 MicroRNAs in Cancer
		7.2.2 Biomarkers and Their Usefulness in Cancer Diagnosis
		7.2.3 Functions
		7.2.4 Therapy
	7.3 miRNAs Responsible for Cancer Aggressiveness
	7.4 miRNAs, Epigenetic Mechanisms, and Cancer Aggressiveness
	7.5 Hypoxia Microenvironment
	7.6 Hypoxia and Cancer Aggressiveness
		7.6.1 Blood Vessel Formation
		7.6.2 Metastasis
		7.6.3 Radiation and Drug Resistance
	7.7 microRNAs and Hypoxia Microenvironment
	7.8 The Stem cells, Cancer Aggressiveness, and Hypoxia
	7.9 miRNAs, Hypoxia, Stem-Like State, and Their Role in Therapeutics
	7.10 Exosomal MicroRNAs in Cancer
		7.10.1 Exosomal miRNAs Affect Chemotherapeutic Resistance in Cancer Cells
		7.10.2 Exosomal miRNAs Can Be Used for Diagnosis and Prognostication of Cancers
	7.11 MicroRNAs as Potential Therapeutics Against Cancer
		7.11.1 miRNA Inhibition Therapy
		7.11.2 miRNA Restoration Therapy
	References
8: piRNA-Based Cancer Therapy in Hypoxic Tumor
	8.1 Introduction
	8.2 Biogenesis of piRNAs and Generation of Mature piRNAs
	8.3 piRNAs: Novel Functions in Cancer Expression and Selectively Deregulation by Hypoxic Tumors
	8.4 piRNAs Maintain Genomic Integrity by Silencing Transposable Elements
	8.5 piRNAs Contribute to Tumorigenesis Through Regulation of DNA Methylation
	8.6 Post-Transcriptional Regulation of Gene Expression by piRNAs
	8.7 piRNAs Have Tumorigenic or Suppressive Roles in Cancer Development
	8.8 piRNAs in the Maintenance of Cancer Stemness and Chemoresistance
	8.9 The Role of piRNAs in Hypoxic Cancer
	8.10 Gastric Cancer
	8.11 Bladder Cancer
	8.12 Breast Cancer
	8.13 Lung Cancer
	8.14 Liver Cancer
	8.15 Stomach Cancer
	8.16 Colorectal Cancer
	8.17 PIWIs May Be Used for Cancer Diagnosis and Prognosis
	8.18 piRNAs as Biomarkers in Cancer Potential Clinical Applications of piRNAs as Cancer Biomarkers
	8.19 New Therapeutic Approaches Using piRNAs
	8.20 Database for piRNAs and Functional Predictions
	8.21 Future Directions in piRNA Research in Hypoxic Oncology
	References
9: Hypoxia and the Metastatic Cascade
	9.1 Life of a Cancer Cell in the Hypoxic Tumour Microenvironment and Beyond
		9.1.1 Manifestation of Metastasis
		9.1.2 Cellular Characteristics of a Metastatic Cancer Cell
		9.1.3 Fate of a Cancer Cell
		9.1.4 The Dormant Cancer Cell and Plastic Cancer Stem Cell
		9.1.5 Role of Hypoxia in Determining the Fate of a Cancer Cell
	9.2 Hypoxia Orchestrates the Metastatic Cascade
		9.2.1 The Invasive Phenotype and EMT
		9.2.2 Local Invasion of Cancer Cells
		9.2.3 Intravasation into Blood Vessels
		9.2.4 Moving to a New Home: Extravasation from Blood Vessel to Secondary Site
		9.2.5 Pre-metastatic Niche Formation
		9.2.6 Metabolic Reprogramming During Metastasis
		9.2.7 Chemoresistance and Poor Prognosis
		9.2.8 Immune Evasion by Programming
		9.2.9 Epigenetic Changes Regulating Metastasis
	9.3 Case Study: Hypoxia in Breast Cancer Metastasis
	9.4 Advances in Hypoxia-Related Drug Development Research Against Metastatic Cancers
		9.4.1 Treatment Challenges in Metastatic Cancers
		9.4.2 Recent Advances in Technology
		9.4.3 Recent Advancements in Drug Development in Context of Hypoxia-Driven Metastasis
			9.4.3.1 Nanomaterial
			9.4.3.2 Antibodies
			9.4.3.3 Antibody Drug Conjugate
			9.4.3.4 Prodrugs
			9.4.3.5 Drugs Targeting Hypoxia
			9.4.3.6 Biomedical Devices
		9.4.4 Promising Strategies for Drug Development
	9.5 Concluding Remarks
	References
10: Hypoxia and Extracellular Matrix-Major Drivers of Tumor Metastasis
	10.1 Introduction
	10.2 Hypoxia
		10.2.1 Causes of Hypoxia in Tumor Microenvironment
		10.2.2 Cellular Adaptations to Hypoxic States
		10.2.3 Hypoxia and HIF Signaling
		10.2.4 The Role of Hypoxia in Cancer Development
		10.2.5 Hypoxic Signaling Promotes Metastasis
			10.2.5.1 Evasion of Immunity
			10.2.5.2 Invasion
			10.2.5.3 Intravasation and Extravasation
			10.2.5.4 The Premetastatic Niche and HIF Signaling
			10.2.5.5 HIF Signaling, Cellular Development, and Life at a Distant Area
	10.3 ECM
		10.3.1 Components of the Extracellular Matrix (ECM)
		10.3.2 Remodeling Mechanisms of ECM in TME
		10.3.3 The ECM Modifications During Metastasis
			10.3.3.1 Invasion of Cancer Cells Through Basement Membranes
			10.3.3.2 ECM Remodeling in Circulation
			10.3.3.3 ECM Remodeling in Premetastatic Niche
			10.3.3.4 ECM Remodeling in Metastatic Niche
	10.4 Phytochemicals Targeting HIFs and ECM in TME
	10.5 Conclusion
	References
11: Role of Hypoxia in Cancer Therapy: Introduction
	11.1 Introduction
	11.2 Hypoxia-Inducible Factor
	11.3 Tumor Angiogenesis
	11.4 Metabolic Derangement
	11.5 Tumor Immune Response
	11.6 Tumor Metastasis
	11.7 Chemoresistance
	11.8 Hypoxia and Drug Resistance
	11.9 Hypoxia and New Treatment Modalities
	11.10 Hypoxia-Activated Prodrugs
	11.11 Drugs Targeting Hypoxic Signaling
	11.12 Topoisomerase 1 Inhibitors
	11.13 Heat Shock Protein Inhibitors
	11.14 Inhibitors of HIF Transcriptional Activity
	11.15 Proteasome Inhibitors
	References
12: Hypoxic Regulation of Telomerase Gene Expression in Cancer
	12.1 Introduction
	12.2 Telomeres in Hypoxic Cancer
	12.3 Connection Between Hypoxia and the Stimulation of Telomerase Activity
	12.4 Expression of hTERT Is Stimulated by Hypoxia, and HIF1 Interacts with Putative HREs in the hTERT Promoter
	12.5 In Telomerase-Deficient Animal Model, Telomere-Based Crises Increase Tumorigenesis
	12.6 Copy Number Changes, Translocations, and Telomere Dysfunction
	12.7 Telomere Dynamics and Genomic Changes in Hypoxic Breast Cancer
	12.8 Telomerase Reactivation Plays Two Unique Roles in Hypoxia-Induced Cancer
	12.9 Effect of Increased HIF-1a Expression on Telomerase Gene Promoter Expression
	12.10 Effect of Hypoxia on the Telomerase Genes´ Endogenous Expression
	12.11 Identification of HIF-1 Binding to the Promoters of the Telomerase Genes
	12.12 Under Hypoxic Circumstances: The Telomerase Genes and the Transcriptional Complex
	12.13 Telomerase as a Hypoxic Cancer Target: Challenges and Opportunities
	12.14 Anticancer Strategies Targeting Telomerase in Hypoxic Cancer
	12.15 Conclusion and Future Aspect
	References
13: CRISPR/Cas9-Editing-Based Modeling of Tumor Hypoxia
	13.1 Introduction
	13.2 Tumor Hypoxia
	13.3 CRISPR/Cas9 Technology: A Gene-Editing Tool
	13.4 Hypoxia-Specific Expression of CRISPR-Cas9
	13.5 Genome-Wide CRISPR/Cas9 Screening and Progression of Hypoxic Cancer
	13.6 Knockdown of Hypoxia-Inducible Genes by Tumor Target Delivery of CRISPR/Cas9 System
	13.7 CRISPR/Cas9-Mediated Hypoxia-Inducible Factor-1α Knockout Enhances the Antitumor Effect
	13.8 HIF-1α-Knockout via CRISPR/Cas9 Suppresses HIF-1α Expression and Impairs Cell Invasion and Migration
	13.9 CRISPR/Cas9-Based HIF-1α Disruption Suppresses Cell Proliferation and Induces Cell Apoptosis
	13.10 Hypoxia-Responsive Gene Editing to Reduce Tumor Thermal Tolerance for Mild Photothermal Therapy
	13.11 Genome-Wide CRISPR/Cas9 Deletion Screen for Tumor Cell Viability in Hypoxia
	13.12 CRISPR/Cas9-Mediated Altered Expression of HIF-1α Enhances the Antitumor Effect
	13.13 Future Outlook
	References
14: Tumor-on-a-Chip: Microfluidic Models of Hypoxic Tumor Microenvironment
	14.1 Introduction
	14.2 3D Tumor Models on Chip for Measurement of Hypoxia
		14.2.1 Conventional Transwell Model
		14.2.2 Tumor Spheroids
		14.2.3 Cancer Three-Dimensional Cell Culture in 3D Matrices
	14.3 Tumor-Microvascular Model in Microfluidics
		14.3.1 Mimicking TME Using Microfluidic Devices
		14.3.2 Modeling Hypoxia and Necrosis
	14.4 Application of Tumor-on-a-Chip
		14.4.1 Multiplexed Drug Screening
		14.4.2 Transport and Delivery of Nanoparticles
		14.4.3 Microfluidic Devices for the Analysis of Transcriptomic and Proteomic Factor
	14.5 Challenges and Future Prospects
	14.6 Conclusion
	References
15: Imaging the Hypoxic Tumor Microenvironment in Cancer Models
	15.1 Introduction
	15.2 Mechanism of Hypoxia in Tumors
	15.3 Approaches for Imaging Tumor Hypoxia
		15.3.1 Invasive Approaches
			15.3.1.1 Oxygen Polarographic Electrodes
			15.3.1.2 Phosphorescence Quenching
		15.3.2 Endogenous Markers of Hypoxia
			15.3.2.1 Hypoxia-Inducible Factor
			15.3.2.2 Carbonic Anhydrase IX
			15.3.2.3 Glucose Transporter-1
			15.3.2.4 Osteopontin
			15.3.2.5 Pimonidazole
		15.3.3 Noninvasive Approaches
			15.3.3.1 MRI-Based Measurements
			15.3.3.2 Near-Infrared Spectroscopy/Tomography
			15.3.3.3 Photoacoustic Tomography (PAT)
			15.3.3.4 Hypoxia PET Imaging
	15.4 Pits and Falls of Hypoxia Imaging
	15.5 Challenges and Future Prospects
	15.6 Conclusion
	References
16: Hypoxia-Targeting Drugs as New Cancer Chemotherapy Agents: Molecular Insights
	16.1 Introduction
	16.2 Hypoxia-Induced Cellular Signaling Pathways
	16.3 Role of Hypoxia in Tumor Progression
	16.4 Role of Hypoxia in Tumor Metastasis
	16.5 Role of Hypoxia in Resistance to Therapies
		16.5.1 Resistance to Chemotherapy
		16.5.2 Resistance to Radiotherapy
		16.5.3 Resistance to Immunotherapy
	16.6 Hypoxia-Targeting Drugs
		16.6.1 Hypoxia-Targeting Enzyme-Based Prodrug as a New Chemotherapeutic Drug
		16.6.2 Peptide-Based Drugs for Hypoxic Treatment in Cancer
		16.6.3 Hypoxia-Targeted Quinone-Based Drugs
	16.7 Clinical Perspective of Hypoxia in Cancer
	16.8 Summary and Conclusion
	References
17: Identification of Hypoxia-Targeting Drugs in the Tumor Microenvironment and Prodrug Strategies for Targeting Tumor Hypoxia
	17.1 Introduction
		17.1.1 Proteins Involved in Inducing Hypoxic Cancer Cells
		17.1.2 Challenges of Hypoxic Tumor Treatment
	17.2 Bio-Reductive Prodrugs as Hypoxia-Selective Anticancer Agents
		17.2.1 Organic Molecules as Bio-Reductive Hypoxia-Selective Anticancer Prodrugs
		17.2.2 Transition Metal Complexes as Bio-Reductive Hypoxia-Selective Anticancer Agents
			17.2.2.1 Platinum Complexes as Hypoxia-Selective Prodrugs
			17.2.2.2 Cobalt Complexes as Hypoxia-Selective Prodrugs
				17.2.2.2.1 Ternary Co(III) Complexes with Bidentate Anticancer Agents
					17.2.2.2.1.1 Cyclen- and Cyclam-Based sp3 N,N,N,N Donor Ternary Co(III) Complexes
					17.2.2.2.1.2 Tpa- and Tren-Based sp2 N,N,N and sp3 N Donor Ternary Co(III) Complexes
					17.2.2.2.1.3 Bimetallic N,N,N,N Donor Ternary Co(III) Complexes
				17.2.2.2.2 Bio-Reductive Co(III) Complexes with Acetylacetonate Ligands
					17.2.2.2.2.1 Binary Co(III) Complexes with Acetylacetonate and Nitrogen Mustard Ligands
					17.2.2.2.2.2 Binary Co(III) Complexes with Acetylacetonate and Other Bidentate Ligands
				17.2.2.2.3 Co(III) Complexes with Schiff Base Ligands
				17.2.2.2.4 Co(III) Complex with Phenanthroline-Based Ligands
				17.2.2.2.5 Other Types of Co(III) Complexes with Anticancer Activities
	17.3 Summary and Conclusion
	References
18: Hypoxia-Induced Apoptosis in Cancer Development
	18.1 Apoptosis
		18.1.1 Intrinsic Pathway
		18.1.2 Extrinsic Pathways
			18.1.2.1 FAS Pathway of Apoptosis
			18.1.2.2 TNF Pathway of Apoptosis
		18.1.3 Evasion of Apoptosis in Tumor Cells under Hypoxic Condition
	18.2 Apoptosis Reprogramming under Hypoxia
		18.2.1 Hypoxia-Inducible Factor (HIF): The Master Regulator of Hypoxic World and Apoptosis
			18.2.1.1 Hypoxia-Inducible Factors
			18.2.1.2 HIF Regulation
				18.2.1.2.1 HIF Regulation Under Normoxic Condition
				18.2.1.2.2 HIF Regulation under Hypoxic Condition
			18.2.1.3 HIF and Apoptosis
		18.2.2 p53 and HIF: Communications among Master Regulators
			18.2.2.1 HIF and p53 Interaction in Cancer Progression
		18.2.3 HIF-Independent Response
			18.2.3.1 Allosteric regulation of glycolytic enzymes
			18.2.3.2 Alternate Glucose Uptake and Creatine Metabolism During Hypoxic Conditions
			18.2.3.3 Myc and HIF-1 Deficiency
	18.3 HIF and Apoptosis in Physiological and Pathophysiological Conditions
		18.3.1 Role of HIF in Physiological and Pathophysiological Conditions
			18.3.1.1 Role of HIF in Cancer
			18.3.1.2 Overexpression of HIF-1α in Human Cancers
	18.4 Implications for Cancer Therapy
	18.5 Implication of Cancer Therapy Targeting HIF
	18.6 Conclusion
	References
19: Hypoxia in Drug Resistance and Radioresistance
	19.1 Introduction
	19.2 Hypoxia, Apoptosis, and Drug Resistance
	19.3 Hypoxia, Cell Cycle Arrest, Senescence, and Drug Resistance
	19.4 Hypoxia, Metabolic Programming, and Drug Resistance
	19.5 Hypoxia, Angiogenesis, and Drug Resistance
	19.6 Hypoxia, Intratumoral Immunity, and Immunotherapy
	19.7 Hypoxia and Radiation Therapy Resistance
	19.8 Conclusion
	References