Cytokine and Chemokine Networks in Cancer

Foreword
Preface
	Introduction to the Book
	Target Audience
	Importance of the Book
	Highlights of the Book
Acknowledgments
Contents
Editor and Contributors
About the Editor
Contributors
1: Introduction to Cytokine and Chemokine Networks
	1.1	 An Overview of Cytokines
	1.2	 Why Do Cytokines Have Such a Diverse Range of Functions?
	1.3	 Characteristics of the Cytokine Network
	1.4	 A Classification of Cytokines and an Analysis of Their Clinical Importance
		1.4.1	 Pro-Inflammatory Cytokines
		1.4.2	 Anti-Inflammatory Cytokines
	1.5	 Chemokines
		1.5.1	 Chemokines: A Unique Instance of Complexity
		1.5.2	 Genomic Organization of Chemokines and Their Functional Complexity
		1.5.3	 Chemokine Receptors
			1.5.3.1	 Conventional Chemokine Receptors
			1.5.3.2	 Atypical Chemokine Receptors
		1.5.4	 The Role of the Chemokine Network
	1.6	 Cytokines and Chemokines for Cancer Therapy
	1.7	 Conclusions
	References
2: Cytokines and Chemokines in Tumor Growth and Progression
	2.1	 Introduction
	2.2	 Cytokine Receptors
	2.3	 Types of Cytokines
	2.4	 Interferons
		2.4.1	 Interferons and Cancer
			2.4.1.1	 Type I IFN Signaling and Cancer
		2.4.2	 Type I IFNs
		2.4.3	 IFN-γ and Cancers
	2.5	 Tumor Necrosis Factors
	2.6	 Interleukins
	2.7	 Cytokines as the Key Components in Cancer-Related Inflammation
	2.8	 Cytokines and Cancer: TNF and Interleukin-1
		2.8.1	 Cytokines and Cancer: IL-6
		2.8.2	 Cytokines and Cancer: IL-10, TGF-β, and IL-23
	2.9	 Chemokines
		2.9.1	 The Structure of Chemokines
		2.9.2	 Chemokine Types and Their Receptors
		2.9.3	 The Roles of the CCL2/CCR2 Signaling Axis in Tumor Progression
		2.9.4	 The Role of the CCL5/CCR5 Axis in Cancer Progression
		2.9.5	 The Roles of CCL19/CCL21/CCR7 in Cancer Progression
		2.9.6	 The Role of CCL20/CCR6 in Cancer Progression
		2.9.7	 Chemokines in EMT
		2.9.8	 Chemokines in Tumor Growth
		2.9.9	 Chemokines in Angiogenesis
		2.9.10	 Chemokines in Metastasis
		2.9.11	 CCL19/CCL21
		2.9.12	 CCR9–CCL25
		2.9.13	 CCR10–CCL27/CCL28
		2.9.14	 CXCR3–CXCL9, CXCL10, and CXCL11
	2.10	 Cytokines and Breast Cancer
	2.11	 Conclusions
	References
3: Chemokine and Cytokine Network in Angiogenesis
	3.1	 Introduction
	3.2	 Regulators of Angiogenesis
		3.2.1	 Family of Vascular Endothelial Growth Factors (VEGF)
		3.2.2	 Angiopoietin (Ang)–Tie System
		3.2.3	 Hepatocyte Growth Factor (HGF)
		3.2.4	 Fibroblast’s Growth Factor (FGF)
		3.2.5	 Platelet-Derived Growth Factor (PDGF)
			3.2.5.1	 Interleukins: An Immune System and Angiogenesis Connection
			3.2.5.2	 Interferons and Angiogenesis
			3.2.5.3	 Interleukin-1 Family
	3.3	 C Family
	3.4	 Interleukin 6 Family
	3.5	 Family of Interleukin-17
	3.6	 Interleukin 12 Family
	3.7	 Family of Interleukin-10
	3.8	 Chemokines: Role in Angiogenesis
	3.9	 C-X-C Chemokines
	3.10	 CXCL8: Role in Angiogenesis
	3.11	 C-C Chemokine
	3.12	 Chemokine CX3C
	3.13	 Cancer Therapies That Focus on Angiogenesis
		3.13.1	 VEGF Family: The Targeting Therapies
	3.14	 Therapies for Targeting Angiopoietin
	3.15	 Therapies Targeting HGF
	3.16	 Therapies for FGF Targeting
	3.17	 Therapies for PDGF
	3.18	 Conclusion
	References
4: Implications of Chemokine Heterogenicity in Cancer Metastasis
	4.1	 Introduction
	4.2	 The Spectrum of Cancer Heterogenicity
		4.2.1	 Clinicopathological Heterogeneity and Its Molecular Basis
		4.2.2	 Clonal Evolution as a Model of Tumor Progression and Heterogeneity
		4.2.3	 Tumor Heterogeneity: A Dynamic State
	4.3	 Existence of Tumor Heterogeneity at Various - Omics Levels
		4.3.1	 Genomic Heterogeneity
		4.3.2	 Heterogenicity of Transcription
		4.3.3	 Proteomic Heterogeneity
	4.4	 Current Evidence for Intratumor Heterogeneity
	4.5	 The Genomic Relationship Between Primary and Metastatic Tumors
	4.6	 Implications for Targeted Therapeutics
		4.6.1	 Secondary Somatic Mutation Heterogeneity and Medication Resistance
		4.6.2	 Tumor Heterogeneity and the Validation of Biomarkers for Targeted Therapy
		4.6.3	 Utilizing the Therapeutic Potential of Intratumor Heterogeneity
	4.7	 Therapeutic Opportunities Targeting the Metastasis–Metabolism Cross Talk in Cancer
		4.7.1	 Isocitrate Dehydrogenase (IDH)1/2 Inhibitors
		4.7.2	 Lipid Metabolism Inhibitors
		4.7.3	 Cholesterol Metabolism Inhibitors
		4.7.4	 S-Adenosylmethionine (SAM) Cycle Inhibitors
		4.7.5	 Nucleotide Metabolic Inhibitors
		4.7.6	 Glycogenolysis and Gluconeogenesis Inhibitors
	4.8	 Conclusions
	References
5: The Role of Interleukin (IL)-6/IL-6 Receptor Axis in Cancer
	5.1	 Introduction
	5.2	 IL-6 and Its Receptor Structure
	5.3	 IL-6 Signaling in Cancer
	5.4	 Classical Signaling and Trans-Signaling
	5.5	 Signaling Pathway for IL-6/JAK/STAT3
	5.6	 How IL-6 Regulates Tumor Progression
	5.7	 Inflammation Promotes Cancer
		5.7.1	 IL-6 Promotes Invasion, Metastasis, and Angiogenesis
		5.7.2	 At Elevated Levels, IL-6 Acts as a Prognostic Marker for Various Cancers
			5.7.2.1	 Colon Cancer
			5.7.2.2	 Breast Cancer
			5.7.2.3	 Ovarian Cancer
			5.7.2.4	 Other Types of Cancers
	5.8	 IL-6/IL-6R Axis Targeting in Cancer
	5.9	 JAK Inhibitors
	5.10	 STAT3 Inhibitors
	5.11	 Conclusions
	References
6: The Interleukin-8 Pathway in Cancer
	6.1	 Introduction
	6.2	 The Structure of Interleukin-8
	6.3	 IL-8 Receptors
		6.3.1	 CXCR1
		6.3.2	 CXCR2
		6.3.3	 The CXCL8–CXCR1/2 Signaling Pathway
	6.4	 NF-κB’s Role in IL-8 Signaling
	6.5	 Interleukin-8 (IL-8) and Integrin β3
	6.6	 CXCL8 in the Tumor Microenvironment
	6.7	 Cancer Stem Cells (CSCs)/IL-8
	6.8	 Neutrophils/IL-8
	6.9	 IL-8/Myeloid-Derived Suppressor Cells (MDSCs)
	6.10	 IL-8 and Epithelial–Mesenchymal Transition
	6.11	 Inflammation/Tissue Injury/CXCL8
	6.12	 Promoting Tumorigenic Angiogenesis
	6.13	 CXCL8 in Tumor Biology
	6.14	 The Role of IL-8 in Breast Cancer
	6.15	 The Role of IL-8 in Ovarian Cancer
	6.16	 The Role of IL-8 in Prostate Cancer
	6.17	 The Role of IL-8 in Nonpathogenic Situations
	6.18	 IL-8 as a Universal Indicator
		6.18.1	 IL-8 as a Marker for Urinary Bladder Cancer
		6.18.2	 IL-8 as a Marker for Non-Hodgkin’s Lymphoma’ (NHL)
		6.18.3	 IL-8 as a Marker for Nosocomial Infections
		6.18.4	 IL-8 as an Indicator of Acute Pyelonephritis
		6.18.5	 Recognition of Pulmonary Infections
		6.18.6	 Recognition of Osteomyelitis
	6.19	 IL-8-Targeting Immunotherapy
	6.20	 Future Directions
	6.21	 Conclusions
	References
7: CXCL12–CXCR4 Axis in Cancer Metastasis
	7.1	 Introduction
	7.2	 How Tumor Cells Circumvent the Immune System
		7.2.1	 Avoiding Immune Recognition
		7.2.2	 Instigating an Immunosuppressive Tumor Microenvironment
	7.3	 Cancer Proliferation and the CXCR4/CXCL12/CXCR7 Chemokine Axis
		7.3.1	 CXCL12, CXCR4, and CXCR7
	7.4	 C-X-C Motif Chemokine 12 (CXCL12) Receptors
		7.4.1	 Chemokine Receptor CXCR4
	7.5	 Chemokine Receptor CXCR7/RDC-1
	7.6	 Transduction of the C-X-C Motif Chemokine Ligand 12 (CXCL12) Axis
		7.6.1	 Cancer-Related CXCL12 and the CXCR7/CXCR4/Axis
			7.6.1.1	 Breast Cancer
			7.6.1.2	 Prostate Cancer (PCa)
			7.6.1.3	 Lung Cancer
			7.6.1.4	 Other Cancers
	7.7	 C-X-C Motif Chemokine Ligand 12 (CXCL12) Axis in Tumor Cell Growth, Survival, and Tumor Progression
	7.8	 C-X-C Motif Chemokine Ligand 12 (CXCL12) Axis in Invasion and Metastasis
	7.9	 Conclusion
	References
8: CCL5/CCR5 Axis in Cancer
	8.1	 Introduction
	8.2	 Chemokines
	8.3	 Role of CCL5 and CCR5 in Invasiveness
	8.4	 The CCL5/CCR5 Axis and the Progression of Cancer
	8.5	 Tumor Growth
	8.6	 Migration and Extracellular Matrix Remodeling
	8.7	 Drug Resistance, Reduced Cytotoxicity of DNA-Damaging Agents, and Cancer Stem Cell Expansion
	8.8	 Unrestrained Cellular Energy (Metabolic Reprogramming)
	8.9	 Angiogenesis
	8.10	 Immune and Stromal Cell Recruitment as well as Immunosuppressive Polarization
	8.11	 CCL5/CCR5 Axis’s Downstream and Upstream Pathways
	8.12	 Upstream Regulators of CCL5/CCR5
	8.13	 The Tumor-Promoting Role of the CCL5/CCR5 Axis
	8.14	 The CCL5/CCR5 Axis in Hematological Malignancies
	8.15	 Acute Myeloid Leukemia
	8.16	 Chronic Lymphoblastic Leukemia and Acute Lymphoblastic Leukemia
	8.17	 Hodgkin Lymphoma
	8.18	 The CCL5/CCR5 Axis in Solid Tumors
		8.18.1	 Breast Cancer
		8.18.2	 Colon Cancer
		8.18.3	 Gastric Cancer
		8.18.4	 Lung Cancer
		8.18.5	 Osteosarcoma
		8.18.6	 Ovarian Cancer
		8.18.7	 Prostate Cancer
		8.18.8	 Thyroid Cancer
	8.19	 Possible Clinical Applications: CCL5 and CCR5 as Therapeutic Targets in Cancer
	8.20	 Conclusion
	References
9: CCL2–CCR2 Signaling Axis in Cancer
	9.1	 Introduction
	9.2	 Biological Characteristics of CCR2 and CCL2
	9.3	 CCL2 Amplification by the Activation of the AKT-STAT 3 Signalling Pathway and Its Relation to Cancer Metastasis
	9.4	 CCL2–CCR2 and Cancer Progression
		9.4.1	 CCL2–CCR2 and Prostate Cancer
		9.4.2	 CCL2 CCR2 and Breast Cancer
		9.4.3	 CCL2–CCR2 and Colorectal Cancer
		9.4.4	 CCL2–CCR2 and Other Cancers
	9.5	 CCL2–CCR2 and TME
		9.5.1	 Monocytes
		9.5.2	 Neutrophils
		9.5.3	 Myeloid-Derived Suppressor Cells (MDSCs)
		9.5.4	 T Lymphocytes
		9.5.5	 Fibroblasts
	9.6	 CCL2–CCR2 Axis as a Therapeutic Target
		9.6.1	 Targeting CCL2–CCR2 Pathway
			9.6.1.1	 Suppression of CCL2
			9.6.1.2	 Suppression of CCR2
	9.7	 Conclusion
	References
10: CXCL9, CXCL10, CXCL11/CXCR3 Axis and Immune Activation
	10.1	 Introduction
	10.2	 CXCL9, CXCL10, CXCL11, and CXCR3 Expression and Implication
	10.3	 Immune Response Axis of CXCL9, CXCL10, and CXCL11/CXCR3
	10.4	 Cancer Treatment and CXCL9, CXCL10, and CXCL11/CXCR3 Axis
	10.5	 Immune Pathway Enhancers and CXCL9, CXCL10, and CXCL11/CXCR3 axis
	10.6	 Conclusion
	References
11: Role of the CXCL8–CXCR1/2 Axis in Cancer and Inflammatory Diseases
	11.1	 Introduction
	11.2	 CXCL8
		11.2.1	 Structural Characteristics of CXCL8
		11.2.2	 Synthesis and Secretion of CXCL8
	11.3	 The CXCL8 Receptors: CXCR1 and CXCR2
		11.3.1	 Activation of CXCR1 and CXCR2
		11.3.2	 CXCR1 and CXCR2 Regulation
	11.4	 Receptor Transactivation
	11.5	 CXCR1 and CXCR2 Structural Features
		11.5.1	 The CXCR1/2 N-Terminus
		11.5.2	 The C-Terminus of CXCR1/2
	11.6	 Role of CXCL8–CXCR1/2 Axis in Infection
	11.7	 The CXCL8–CXCR1/2 Axis in Cancer
	11.8	 CXCL8–CXCR1/2 Axis and the Tumor Microenvironment
	11.9	 Interactions of the CXCL8–CXCR1/2 Axis and CAF
	11.10	 CXCL8–CXCR1/2 Axis in Immunogenic Cell Death
	11.11	 Immunecheckpoint Inhibition and CXCL8–CXCR1/2 Axis
	11.12	 CXCL8–CXCR1/2 Axis and Cancer Stem Cell
	11.13	 Inflammatory Diseases and the CXCL8–CXCR1/2 Axis
	11.14	 Chronic Obstructive Pulmonary Disorder
		11.14.1	 Asthma
		11.14.2	 Cystic Fibrosis (CF)
		11.14.3	 Inflammatory Bowel Diseases
		11.14.4	 Neuroinflammatory Diseases
		11.14.5	 Vascular Diseases
		11.14.6	 Arthritis
		11.14.7	 Psoriasis
		11.14.8	 Other Inflammatory Disorders
	11.15	 Therapeutic Targeting of the CXCL8–CXCR1/2 Axis in Cancer
	11.16	 Conclusion
	References
12: Chemokine and Cytokine Networks in Tumor Microenvironment
	12.1	 Introduction
	12.2	 Types of Cytokines
		12.2.1	 Interferon
			12.2.1.1	 Type-1 Interferon
			12.2.1.2	 Type 2 Interferon
		12.2.2	 Interleukin
			12.2.2.1	 Tumor Necrosis Factor
	12.3	 Cytokine Signalling
	12.4	 Chemokine Signalling
	12.5	 Building Blocks and Signal Transmission
	12.6	 The Roles of Chemokine Signalling in Cancer Development
	12.7	 Tumor Growth and Progression
	12.8	 Angiogenesis
	12.9	 Metastasis
	12.10	 Tumor Microenvironment
	12.11	 Chemokines in Tumor Microenvironment
	12.12	 Role of Chemokines in Cancer Therapy
	12.13	 CXCR4 and Its Ligand CXCL12
	12.14	 Conclusion
	References
13: Prognostic and Diagnostic Significance of Chemokines and Cytokines in Cancer
	13.1	 Introduction
	13.2	 Cytokine General Characteristics
	13.3	 Cytokine and Cytokine Receptor Classification
	13.4	 Cytokine Receptor Type I
	13.5	 Receptors for Type II Cytokines
		13.5.1	 Superfamily of Immunoglobulin Receptors
	13.6	 Current Immunotherapy Cytokines
	13.7	 The Interferons (IFN)
		13.7.1	 Interferons I Class
		13.7.2	 IFN-α Clinical Applications
		13.7.3	 IFN-β Clinical Potential
		13.7.4	 Interferons II Type
		13.7.5	 IFN-γ Clinical Applications
		13.7.6	 Interferons III Type
	13.8	 Interleukin-2
	13.9	 IL-2 Clinical Applications
	13.10	 IL-2 Predictive Biomarkers
	13.11	 Cytokines Related to IL-2
		13.11.1	 Interleukin-7
		13.11.2	 Interleukin-15
		13.11.3	 Interleukin-21
	13.12	 Additional Cytokines with Clinical Use
		13.12.1	 Interleukin-6
		13.12.2	 Interleukin-18
	13.13	 GM-CSF or Granulocyte-Macrophage Colony-Stimulating Factor
	13.14	 Chemokines and Chemokine Receptors
	13.15	 Chemokine System\'s Impact on Cancer Prognosis
		13.15.1	 CCL2
		13.15.2	 CCL5
		13.15.3	 CCL14
		13.15.4	 CCL20
		13.15.5	 CCR7
		13.15.6	 CXCL1
		13.15.7	 CXCL8
		13.15.8	 CXCL10
		13.15.9	 CXCL12/CXCR4
		13.15.10	 CX3CL1/CX3CR1
		13.15.11	 XCL1
	13.16	 Conclusions
	References
14: Therapeutic Implications of Cytokines and Chemokines Network in Cancer
	14.1	 Introduction
	14.2	 Overview of Cytokines
	14.3	 Family of Cytokines
		14.3.1	 Interleukins
		14.3.2	 Interferon
		14.3.3	 Growth Agent
		14.3.4	 Tumor-necrosis Factor (TNF)
		14.3.5	 Chemokine
	14.4	 Cytokine Receptor
		14.4.1	 Superfamily of Chemokine Receptors
	14.5	 A Cytokine Network during the Development of a Metastatic Niche
	14.6	 Cancer and Cytokine
		14.6.1	 IL-2 and Cancer
		14.6.2	 IL-6 and Cancer
		14.6.3	 IL-8 in Cancer
		14.6.4	 Cancer and IL-10
		14.6.5	 IL-12 and Cancer
		14.6.6	 IL-18 and Cancer
		14.6.7	 TNF-Alpha and Cancer
		14.6.8	 TGF-Beta and Tumor
		14.6.9	 Interferon-gamma and Cancer
		14.6.10 CXCR4 and Cancer
		14.6.11 Cytokines in the Treatment of Cancer
	14.7	 Interferons
		14.7.1	 Application of IFN Alpha in Medicine
		14.7.2	 IL-15 in the Treatment of Cancer
	14.8	 Approaches to Improve Cytokine-Based Therapy
	14.9	 Cytokine Network, Breast Cancer Stem Cells, and Tumor Microenvironment
	14.10	 Cytokine Networks as Important Regulators in Breast Cancer Stem Cells
	14.11	 Current Use of Chemokines in Cancer Therapy
	14.12	 Future Role of Chemokines
	14.13	 Conclusion
	References
15: Chemokines in Cancer Therapy
	15.1	 Introduction
	15.2	 Chemokines
		15.2.1	 CC Chemokine
		15.2.2	 C Chemokines
		15.2.3	 CXC Chemokines
		15.2.4	 CX3C Chemokines
	15.3	 Chemokine Receptors
		15.3.1	 A Conventional Chemokine Receptor
		15.3.2	 A Typical Chemokine Receptor
	15.4	 Tumor Microenvironment and Chemokines
	15.5	 Cells of the Immune System in Tumor Milieu
		15.5.1	 Natural Killer Cells
		15.5.2	 Macrophages
		15.5.3	 Dendritic Cells
		15.5.4	 Neutrophils
	15.6	 A Summary of cxc and cc Chemokines\' Impact on Cancer and Cancer Milieu
		15.6.1	 Direct Tumor Promoting Role
		15.6.2	 Immune Regulatory Functions
	15.7	 Chemokine Organotropism
	15.8	 Role of Chemokines in Tumor Growth and Progression
		15.8.1	 Leukocyte Recruitment
		15.8.2	 Angiogenesis
		15.8.3	 Tumor Development and Spread
		15.8.4	 Metastasis
	15.9	 Chemokines in Cancer Therapy
		15.9.1	 CCR1
		15.9.2	 CCR2 and CCL2
		15.9.3	 CCR4
		15.9.4	 CCR5
		15.9.5	 CCR7
		15.9.6	 CXCR2
	15.10	 Chemokine Therapy and Breast Cancer
		15.10.1 Studies on Drugs that Target Chemokines and Their Receptors in bc
	15.11	 Conclusion
	References