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