Inflammation and Metastasis

Preface
	Preface (The First Edition, 2016)
	References
Contents
Chapter 1: General Thinking About Inflammation
	1.1 What Is Inflammation?
	1.2 Essence Suggested by the Origin of the Word ``Inflammation´´
	1.3 Pathological View
	1.4 Dynamic Features of Acute Inflammation
		1.4.1 Wound Healing
		1.4.2 Simple Models of Wound Healing in Primitive Lives
		1.4.3 Wound Healing Models in Mammals
		1.4.4 Endotoxin-Degrading Enzyme
		1.4.5 Lipid Mediators
		1.4.6 Direct Neutralization of Mediators by Coagulation Factors
		1.4.7 Clearance of Cell Debris
		1.4.8 Fibrosis
			1.4.8.1 Hippo and Resolution
	1.5 How to Think of Chronic Inflammation
	1.6 Markers of Inflammation
	1.7 Concluding Remarks
	References
Chapter 2: Inflammation from the Standpoint of Leukocytes
	2.1 Definitions
	2.2 Introduction
	2.3 Influenza
	2.4 Influenza and Leukocytes
		2.4.1 Cell Death of Infected Epithelial Cells
		2.4.2 Innate Immunity of Infected Epithelial Cells and NK
		2.4.3 Innate Immunity of Macrophages and DC
		2.4.4 Acquired Immunity by DC, Th, CTL
			2.4.4.1 DC and CTL
			2.4.4.2 Activation of Effector T Cells
			2.4.4.3 Th17
			2.4.4.4 Treg
			2.4.4.5 Adaptive
		2.4.5 DC and Macrophage Responses to Dead Cells
			2.4.5.1 Cell Death
			2.4.5.2 M1 Versus M2
			2.4.5.3 PGE2
		2.4.6 Secondary Infection
			2.4.6.1 Primary and Secondary Infection
			2.4.6.2 Complement Cascade
			2.4.6.3 CRP Receptors
		2.4.7 Neutrophils
		2.4.8 COVID-19
	2.5 Concluding Remarks
	References
Chapter 3: Vessels and Coagulation
	3.1 Vessels
		3.1.1 Introduction
		3.1.2 Adhesion Machinery
			3.1.2.1 Endothelial Adhesion
			3.1.2.2 Caveolae
		3.1.3 Methods for Vascular Permeability
		3.1.4 VEGF
		3.1.5 Extracellular Matrix
		3.1.6 Temporal Factors in Vascular Permeability
		3.1.7 Common and Fundamental Molecular Biology of Vascular Permeability
		3.1.8 Other Permeability Factors
			3.1.8.1 Overview
			3.1.8.2 Hemorrhagic Injury as Represented by Thrombin
			3.1.8.3 TNF
			3.1.8.4 Complement
			3.1.8.5 Bradykinin and Soluble Ephrin-A1
		3.1.9 Antagonism in Vascular Permeability
			3.1.9.1 Antagonist-1:S1P-S1P1 Maintenance of Barrier [19]
			3.1.9.2 Antagonist-2: HGF Maintenance of Barrier [22]
			3.1.9.3 Antagonist-3: Angiopoietin 1 (Ang1) Maintenance of Barrier [23]
		3.1.10 Aquaporin
		3.1.11 Coupling Biology with Endothelial Permeability
	3.2 Coagulation
		3.2.1 Definition
		3.2.2 Endothelial Barrier Against Coagulation
		3.2.3 Basics of Coagulation
			3.2.3.1 Coagulation Cascade
			3.2.3.2 Hemolytic Uremic Syndrome
			3.2.3.3 Connection Between Platelets and Coagulation
			3.2.3.4 Platelet Activation by ECM
				3.2.3.4.1 Overview
				3.2.3.4.2 Collagen-Platelet Adhesion
				3.2.3.4.3 Platelet-Platelet (Aggregation)
		3.2.4 Modulation of Coagulation
	3.3 Triangle of Angiogenesis, Coagulation, and Inflammation
		3.3.1 Overview
		3.3.2 Angiogenesis Affects Coagulation and Inflammation
		3.3.3 Coagulation Affects Angiogenesis and Inflammation
		3.3.4 Inflammation Affects Coagulation and Angiogenesis
	3.4 Concluding Remarks
	References
Chapter 4: Sterile Inflammation
	4.1 Sterile Inflammation
	4.2 Phenomenological Research
		4.2.1 Irradiation
		4.2.2 SLE
		4.2.3 Immunity-Mediated Inflammatory Disorders
			4.2.3.1 Guillain-Barré
			4.2.3.2 Multiple Sclerosis
			4.2.3.3 Pollinosis
			4.2.3.4 Psoriasis
	4.3 X-Ray Effects
	4.4 Analytical Research in Leukocyte Chemotaxis In Vivo
		4.4.1 Real-Time Imaging
		4.4.2 Necessary and Sufficient Logics
		4.4.3 Monocyte-Dependent Neutrophil Extravasation in Lung Model
		4.4.4 Focal Thermal Injury in Liver
		4.4.5 CXCL2-CXCR2 System
		4.4.6 Sterile Inflammation Induced by Necrotic Cells
		4.4.7 Negative Chemotactism
	4.5 Concluding Remarks
	References
Chapter 5: Issue of Self and Non-self
	5.1 Overview
	5.2 Microbes
		5.2.1 DNA and RNA
		5.2.2 Lipopolysaccharide
			5.2.2.1 LBP-CD14-TLR4/MD-2 Cascade (First Biosensor)
				5.2.2.1.1 Dissociation Constant (Kd)
			5.2.2.2 Mutations in TLR4
			5.2.2.3 BPI (Second Biosensor)
			5.2.2.4 TLR Family Constitutes 13 Mammalian Members
			5.2.2.5 Caspase-11 (Third Biosensor)
			5.2.2.6 RAGE (Fourth Biosensor)
			5.2.2.7 Histones (Possible Fifth Biosensor)
		5.2.3 Ancient to Modern Perspective
			5.2.3.1 Limulus
			5.2.3.2 Drosophila melanogaster
			5.2.3.3 Caenorhabditis elegans
		5.2.4 Vitamin B12
	5.3 Plant
		5.3.1 Microtubule-Binding Proteins
			5.3.1.1 Colchicine
			5.3.1.2 Paclitaxel
		5.3.2 Morphine
		5.3.3 Neuronal Sensor for Non-self
	5.4 PAR
	5.5 Isoantigen as an Exogenous Ligand
	5.6 Major Histocompatibility Complex
	5.7 Tumor Immunology and Vaccine
	5.8 Concluding Remarks
	References
Chapter 6: Extension of Endogenous Field
	6.1 Overview
	6.2 Changes in Quantity
	6.3 Changes in Quality
		6.3.1 Crystal
		6.3.2 Amyloid β Fibril
		6.3.3 Oxidized Products
			6.3.3.1 Pharmacological View of Partial Agonist
		6.3.4 End Products of Lipid Oxidation
		6.3.5 Too Much Degraded Extracellular Matrix
			6.3.5.1 Fibronectin
				6.3.5.1.1 Naming of Sugar-Related Molecules
			6.3.5.2 Hyaluronan
	6.4 Beyond Barrier
		6.4.1 DNAs in the Cytoplasm and Sensor
		6.4.2 Intra- to Extracellular Transit
			6.4.2.1 ATP
			6.4.2.2 Heme
			6.4.2.3 HMGB1 and HMGN1: Alarmin Concept and Danger
			6.4.2.4 Intra- to Extraluminal Transit
	6.5 Concept of Adjuvant: Linkage to Acquired Immunity
	6.6 Endogenous Adjuvants
	6.7 Usage of Terms, ``Adjuvant´´ and ``Priming´´
	6.8 Concluding Remarks
	References
Chapter 7: Evidence for Existence of Endogenous TLR4 Ligands
	7.1 Definition
	7.2 Exogenous Versus Endogenous Ligand, Which Is Discovered First?
	7.3 Candidates of TLR4 Ligands
	7.4 Question of Method
		7.4.1 Limulus Amebocyte Lysate (LAL) Test
		7.4.2 Is Polymyxin B Reliably Effective to Remove LPS?
		7.4.3 Boiling
		7.4.4 Believe or Not
	7.5 Good Exemplars for Demonstration
		7.5.1 Biglycan and Decorin
			7.5.1.1 Biochemical Aspect
			7.5.1.2 Cellular Aspect
			7.5.1.3 Animal Studies
			7.5.1.4 Decorin
		7.5.2 HMGB1
			7.5.2.1 Biochemical Aspect
			7.5.2.2 Cellular Aspect
			7.5.2.3 Animal Studies
		7.5.3 S100A8 and S100A9 and SAA3
	7.6 Endogenous Antagonist Candidates
		7.6.1 OxPAPC (See Chap. 6)
			7.6.1.1 CTRP-3
		7.6.2 Gangliosides
			7.6.2.1 Combined Molecules of Lipid and Sugar
		7.6.3 Globotetraosyl-Ceramide (Gb4)
			7.6.3.1 Biochemical Aspect
			7.6.3.2 Cellular Aspect
			7.6.3.3 Animal Studies
	7.7 Some Interpretations of Published Reports
		7.7.1 Lung Injury and TLR4
		7.7.2 Asthma and TLR4
	7.8 An Idea of Sensitizer
	7.9 Other TLRs
	7.10 Concluding Remarks
	References
Chapter 8: Autoinflammatory Disorders
	8.1 Overview
		8.1.1 Fever as a Historical Golden Marker of Inflammation
	8.2 IL-1β in the IL-1 Family
	8.3 Inhibitors of NLRP3
		8.3.1 Nitric Oxide
		8.3.2 Presence of Endogenous IL-1β Inhibitors
	8.4 TNF in the Middle of Large TNF and TNFR Families
		8.4.1 TNF
	8.5 Autoinflammatory Diseases
		8.5.1 Familial Mediterranean Fever
		8.5.2 Deficiency of IL-1 Receptor Antagonist
		8.5.3 TNF Receptor-Associated Periodic Syndrome
		8.5.4 Nakajo-Nishimura Syndrome
		8.5.5 Kawasaki Disease from Japan
		8.5.6 Rheumatoid Arthritis
		8.5.7 Chediak-Higashi Syndrome
		8.5.8 Experimental A20 Deficiency: Antagonism Against NFκB Signaling
	8.6 Organotropism in Inflammatory Diseases
	8.7 Lessons from Patients: Relevance to TLR and Its Endogenous Ligands
	8.8 Linkage Between Autoimmune Disease and Autoinflammatory Disease
	8.9 Concluding Remarks
	References
Chapter 9: Cancer in General
	9.1 Overview
	9.2 Origin and Development
		9.2.1 Cell Type
		9.2.2 Time
		9.2.3 Space
		9.2.4 Clonality
	9.3 Physiological Hematopoiesis
		9.3.1 General Information
		9.3.2 Methods to Assay Self-renewing Ability
			9.3.2.1 Experimental Immunodeficiency Mice
	9.4 Chronic Myeloid Leukemia
		9.4.1 General Information
		9.4.2 Cell Type
			9.4.2.1 HSC: GMP: preB
			9.4.2.2 Clonality
			9.4.2.3 Stem Cell Origin
		9.4.3 Time Onset: CP: BC
		9.4.4 Space: Bone Marrow and Spleen
	9.5 Multiple Myeloma
		9.5.1 Cell Type
		9.5.2 Space and Time
	9.6 Tumor
	9.7 Terms in Genetic Epidemiology
	9.8 Breast Cancer
		9.8.1 Cell Type
		9.8.2 Time
			9.8.2.1 Noncoding RNAs
		9.8.3 Space
			9.8.3.1 CTC-Mediated Hematogenous Spread
			9.8.3.2 Metastasis
	9.9 Clinical Example of Advanced Bladder Cancer
	9.10 Concluding Remarks
	References
Chapter 10: Basic Research
	10.1 Oncogene
		10.1.1 Viral and Cellular Oncogene
		10.1.2 Signal Transduction-Proliferation
		10.1.3 Cell Cycle
		10.1.4 RASopathies
		10.1.5 Endless Division
	10.2 Tumor Suppressor
		10.2.1 What Is Tumor Suppressor?
			10.2.1.1 Definition of Tumor Suppressor
		10.2.2 DNA Repair System as One Arm in DDR
			10.2.2.1 Structural Types of DNA Damages
			10.2.2.2 HR
			10.2.2.3 NHEJ
			10.2.2.4 NER
			10.2.2.5 BER
			10.2.2.6 Mismatch
		10.2.3 Linkage to Aneuploidy (See Chap. 12)
	10.3 Stabilization of Pathological Proteins
	10.4 Cell Death Escape
	10.5 Endless Mitosis
		10.5.1 Senescence Versus Quiescence
	10.6 Altered Metabolism
		10.6.1 Basic Information on Glucose Metabolism
		10.6.2 Principle of Metabolism in Cancer
		10.6.3 Autophagy
		10.6.4 Oncogene and Oncometabolite
			10.6.4.1 Hypoxia (See Fig. 11.3 for Hypoxic Tissues)
		10.6.5 Mitochondrial Functions
			10.6.5.1 Synthesis and Signaling
			10.6.5.2 From Oncocytoma to Metastatic Tumors by mtDNA Mutations
	10.7 Complicated Linkage of Myc and HIF-1α to Metabolism and DDR
	10.8 Breast Cancer
		10.8.1 HER2
		10.8.2 Estrogen Receptor
		10.8.3 Hormone-Dependent Tumors
	10.9 Prostate Cancer
	10.10 Recapitulation of Li-Fraumeni Syndrome by Mutant Mice
	10.11 Integrative Analysis and Precision Medicine
	10.12 Concluding Remarks
	References
Chapter 11: Tumor Microenvironment
	11.1 In the Beginning Were the Tumor Cells
	11.2 Normal Vessel Architectures
	11.3 Tumor Vessel Architectures
	11.4 Means and Modes of Communication
		11.4.1 Diatomic Molecules
			11.4.1.1 O2: Hypoxia in Tissues
			11.4.1.2 NO
			11.4.1.3 CO Is Anti-Inflammatory
		11.4.2 Peptide Growth Factors
		11.4.3 Lipids: PGE2, LTB4
		11.4.4 Microvesicles ``Black Shuttle Bus´´
		11.4.5 Metabolites
		11.4.6 Contact-Dependent Tunneling Nanotubes
	11.5 Tumor Angiogenesis
		11.5.1 VEGF
		11.5.2 VEGF Receptors
		11.5.3 VEGF and ECM
		11.5.4 Additional Co-Receptors for VEGFR
			11.5.4.1 CD44
			11.5.4.2 CD146
			11.5.4.3 Ephrin-B2
		11.5.5 Interplay with Growth Factors
			11.5.5.1 FGF and PDGF
			11.5.5.2 TGFβ, VEGF-A, and VEGF-C
			11.5.5.3 GRK2
		11.5.6 A General Idea on Coordination with Opposite Activity
			11.5.6.1 Maspin
			11.5.6.2 Angiopoietin
			11.5.6.3 Vasohibin-1 (EC-Derived)
			11.5.6.4 Examples of Antagonism-1: VEGF and CXCL4 (=PF4)
			11.5.6.5 Examples of Antagonism-2: VEGF and TSP-1 (Thrombospondin-1)
			11.5.6.6 Examples of Antagonism-3: VEGF and Endosialin
			11.5.6.7 Examples of Antagonism-4: VEGF and IFNγ
			11.5.6.8 Examples of Antagonism-5: VEGF and Sema3A
		11.5.7 Linkage Between Vascular Permeability and Intravasation
	11.6 Blood Lake
		11.6.1 Yoshida Sarcoma
		11.6.2 Hideyo Noguchi
			11.6.2.1 Hemorrhagic Snake Venoms
				11.6.2.1.1 Snake Venoms Are Exogenous ``Blood Lake´´-Makers
			11.6.2.2 MMP (See Table 11.2)
				11.6.2.2.1 MMP-1
				11.6.2.2.2 MMP2
				11.6.2.2.3 MMP9
				11.6.2.2.4 MMP13
			11.6.2.3 ADAM (See Table 11.1)
				11.6.2.3.1 ADAM10
				11.6.2.3.2 ADAM12
				11.6.2.3.3 ADAM15
				11.6.2.3.4 ADAM17 (Also Called TACE)
				11.6.2.3.5 ADAMTS1
				11.6.2.3.6 ADAMTS2
				11.6.2.3.7 ADAMTS9: Potential Tumor Suppression
				11.6.2.3.8 ADAMTS13
			11.6.2.4 MT-MMP
				11.6.2.4.1 MT1-MMP (Also Called MMP14)
				11.6.2.4.2 MT1-MMP in Endothelial Cells (EC) [159, 160]
				11.6.2.4.3 Substrate Specificity in MMPs
				11.6.2.4.4 RECK
				11.6.2.4.5 MT1-MMP Is Shared by Endothelial Cells and Tumor Cells
				11.6.2.4.6 New Strategies for Targeting MMP
				11.6.2.4.7 EMMPRIN, an Upstream Regulator of MMP, in Glioma
				11.6.2.4.8 MT2-MMP
				11.6.2.4.9 MT4-MMP
				11.6.2.4.10 MT6-MMP
	11.7 Vascular Mimicry and Angiotropism
	11.8 Nerve and Tumor Cells
	11.9 Fibroblasts and Tumor Cells
	11.10 Quiescence of Cells in Niche
		11.10.1 HSC
			11.10.1.1 Niche Cells
			11.10.1.2 Neuron
		11.10.2 Endothelial Cells
		11.10.3 Aberrant Stem Cell Pathways in Tumor Cells
			11.10.3.1 CSC: Definition and Overview
			11.10.3.2 Tie2 and MPL
			11.10.3.3 CaR
			11.10.3.4 CD117 (c-Kit)
			11.10.3.5 VLA-4 (α4β1 Integrin)
			11.10.3.6 Nestin
			11.10.3.7 Wnt
			11.10.3.8 Notch
			11.10.3.9 CXCR4 and TLR4
			11.10.3.10 Eph-ephrin
			11.10.3.11 MSC and Tumor Cells
	11.11 Intratumor Heterogeneity and Origin of Metastasis Clones
		11.11.1 Clonal Divergence
		11.11.2 EMT
		11.11.3 HSC Niche Analogy: EphA4 Versus EGFR-CSF1R Loop
	11.12 Concluding Remarks
	References
Chapter 12: Whole-Body Matter
	12.1 Overview
		12.1.1 Inflammatory Carcinoma of Breast
	12.2 Mouse Models
		12.2.1 Terms in Genetics
		12.2.2 Metastasis Models
			12.2.2.1 4 T1 Cells
			12.2.2.2 TS/A Cells
			12.2.2.3 MMTV-PyMT Model
			12.2.2.4 K14-HPV16 Mice Skin Cancer Model
			12.2.2.5 K5-SOS Mice Model of Skin Papilloma
			12.2.2.6 KPC Model of Pancreatic Cancer
			12.2.2.7 RIP-Tag2 Mice in the C57BL/6 Background
			12.2.2.8 HPV16/E2 Mice in the FVB/n Background
			12.2.2.9 HGF-CDK4 (R24C) Model Mice of Malignant Melanoma
			12.2.2.10 PTEN-KO Mice of Prostate Cancer Model
				12.2.2.10.1 TRAMP Model of Prostate Cancer
			12.2.2.11 PDX Models
		12.2.3 Orthotopic Versus Ectopic Model
		12.2.4 Idea of Immune Privilege
		12.2.5 Cancers that Result from Inflammation
			12.2.5.1 K14-HPV16 Transgenic Mouse Model of Skin Carcinogenesis
			12.2.5.2 Helicobacter Felis/C57BL/6 Murine Gastric Cancer Model
	12.3 Basic Issues that Need to Be Addressed
	12.4 Cancer Cachexia
	12.5 Incoming and Outgoing Cells via Circulation
		12.5.1 Immune Attack
			12.5.1.1 Evading Immune Attacks
				12.5.1.1.1 Physical Obstacles
					``Matrix Fibers´´ Physical Block
					``Endothelial Cells´´ Contact Failure
				12.5.1.1.2 Functional Obstacles
					Old Cyclophosphamide-Mediated Tumor Rejection Model
					Immuno-Modulator PD-1
	12.6 Incoming
		12.6.1 Tumor-Associated Macrophage Definition
			12.6.1.1 Overview
			12.6.1.2 Origin of Tissue Macrophages
				12.6.1.2.1 What Is TGL?
			12.6.1.3 M1 and M2 (Fig. 12.1)
			12.6.1.4 The Question of Whether or Not TAM Is Proliferating
		12.6.2 T Cells Affect Macrophages
		12.6.3 Myeloid-Derived Suppressor Cells
			12.6.3.1 Human MDSC
			12.6.3.2 Mouse MDSC Affect T Cells
			12.6.3.3 Active Participation of MDSC in Tumor Progression
		12.6.4 Tumor-Associated Neutrophils (Fig. 12.2)
		12.6.5 DC
			12.6.5.1 Lymphoid Malignancy Without Mutations or Nonmalignancy with a Mutation
		12.6.6 Treg (Nonmyeloid Suppressor)
		12.6.7 Mast Cells
		12.6.8 Eosinophils
	12.7 Outgoing
		12.7.1 Overview
		12.7.2 What Is the Destination of Extravasating Tumor Cells?
			12.7.2.1 Interplay Between Two Organs
			12.7.2.2 Interplay Between Three Organs (Tumor, Marrow, Adipose)
			12.7.2.3 Interplay Between Four Organs (Tumor, Marrow, CNS, Lung)
			12.7.2.4 Molecular Plagiarism by Leukemic Cells in CNS Invasion
			12.7.2.5 Self-Seeding Hypothesis
		12.7.3 Lymphatic Spread
	12.8 Application of the Triangle Idea to Tumor Cells (See Fig. 3.6)
		12.8.1 Tumor Cells Activate Coagulation
		12.8.2 Tumor Cells Activate Angiogenesis
			12.8.2.1 VEGF
			12.8.2.2 Hypoxia
			12.8.2.3 PlGF-VEGFR1-Mediated BMDC Migration
			12.8.2.4 G-CSF
			12.8.2.5 Pericyte Damage
			12.8.2.6 Angiotropism Induction
		12.8.3 Tumor Cells Activate Inflammation
	12.9 Gender Bias in Metastasis
		12.9.1 Gender Identity in General
		12.9.2 Influence on Metastasis
	12.10 Neuronal Effects on Metastasis
	12.11 Concluding Remarks
	References
Chapter 13: Premetastatic Microenvironment
	13.1 Overview
	13.2 Clinical Information
		13.2.1 Stephen Paget 1889 (see Table 9.1)
		13.2.2 Metastatic Features Without Primary Tumors
			13.2.2.1 Cancer of Unknown Primary
			13.2.2.2 Effects of Primary Tumor Resection
		13.2.3 Surgical Effects
	13.3 Experimental Information
	13.4 Concept of Field
		13.4.1 Within a Single Organ
		13.4.2 Primary Inflammatory Lesion Can ``Metastasize´´ to Other Organs
	13.5 Definition of Premetastasis
		13.5.1 Forced Experimental Metastasis
		13.5.2 Premetastasis Experiments
		13.5.3 Narrow and Broad Sense: The Second Definition of Premetastasis
			13.5.3.1 Which Come First: Niche Cells or Metastatic Tumor Cells?
			13.5.3.2 Metastasis Dormancy
				13.5.3.2.1 TSP-1 Keeps Quiescence in Vascular Niche
				13.5.3.2.2 VCAM-1 on Tumor Cells Releases Quiescence
				13.5.3.2.3 Dormancy-Inducing Activity as an Anti-Tumor Effect
			13.5.3.3 Antitumor Activity at Premetastatic Sites
		13.5.4 Dissection of Cell Mobilization and Entry via Endothelial Barrier
		13.5.5 Premetastasis Without Primary Tumor
		13.5.6 Premetastatic LN
		13.5.7 Triangle of Premetastasis (Fig. 13.6)
	13.6 BMDC Are Affected by Tumor-Derived Factors
	13.7 Pseudo-Hypoxia and Pseudo-Starvation in Inflammatory Cells
	13.8 Spatial Issue
	13.9 Concluding Remarks
	References
Chapter 14: What Is Homeostasis?
	14.1 Milieu Intérieur
	14.2 Homeostasis at Different Levels
		14.2.1 Whole-Body Level
			14.2.1.1 Thyroid
			14.2.1.2 Neutrophils
		14.2.2 Organ Level
			14.2.2.1 Heart
			14.2.2.2 Liver
			14.2.2.3 Adipose Tissue
		14.2.3 Cell Level
			14.2.3.1 EGFR
			14.2.3.2 CXCR2
		14.2.4 Molecular Level
			14.2.4.1 NFκB Activation
			14.2.4.2 NFκB Modulators
				14.2.4.2.1 A20 Ubiquitination
				14.2.4.2.2 miR-146a
	14.3 Sterile Inflammation
		14.3.1 Neurogenic Inflammation
		14.3.2 Levels of Inflammation
		14.3.3 Interface Between Microbe (Non-Self) and Host (Self)
			14.3.3.1 Gastrointestinal Tract
			14.3.3.2 Lungs
				14.3.3.2.1 Alveolar Space
				14.3.3.2.2 Club Cells
		14.3.4 Interface Between Transformed Self and Host (Self)
			14.3.4.1 Uric Acid
			14.3.4.2 Adipose Tissue (Low-Grade Inflammation)
	14.4 Chronic Versus Repeated Acute Inflammation
	14.5 Homeostatic Stabilization Controls (Neuronal Sensor Versus LPS)
	14.6 Disturbance of Homeostatic Inflammation
	14.7 Concluding Remarks
	References
Chapter 15: Explanation of Metastasis by Homeostatic Inflammation
	15.1 Local Stimuli
		15.1.1 Irradiation at Primary Sites
		15.1.2 Hepatitis
		15.1.3 Bacteria or Lipopolysaccharide
	15.2 Systemic Stimuli
		15.2.1 Arthritis
		15.2.2 Allergy
		15.2.3 Increased Vascular Permeability in the Lungs
	15.3 Disruption of Local Homeostasis
	15.4 Disruption of Systemic Homeostasis
		15.4.1 VEGFR2-CN-NFATc Homeostatic Feedback by DSCR-1
		15.4.2 Inflammation in Vessels
		15.4.3 AA Metabolites
	15.5 Obesity
	15.6 Homeostatic Mimicry in Cancer
		15.6.1 Insulin Mimicry in Preneoplastic Foci in Liver
		15.6.2 LPS Mimicry in Premetastatic Lungs
			15.6.2.1 Roles of S100A8 (see Figs. 15.1, 15.2, and 15.3)
			15.6.2.2 S100A8 and the Eph-Ephrin System
			15.6.2.3 A Single Match Can Start Fire
	15.7 TLR4-Deficient Phenotypes
	15.8 S100 Family
	15.9 Issue of Multiligand/Multireceptor System
	15.10 Endogenous Modulators
		15.10.1 A20
		15.10.2 ATF3
		15.10.3 CD11b
		15.10.4 Calcineurin
		15.10.5 Akt
	15.11 Serum Amyloid A (SAA) Family
		15.11.1 SAA3 May Exist in Humans
		15.11.2 TLR2 May Function as a Receptor for SAA1 and SAA2
	15.12 Neonatal Switch from Bacteria to Endogenous Mediators
	15.13 MDSC and Premetastasis
	15.14 Hijacking the RANKL-RANK System
	15.15 Connexin Hijacking
	15.16 Milky Spots Hijacking
	15.17 Hormonalization of Autacoids
	15.18 Premetastasis Precedes Danger (Damage)
	15.19 Concluding Remarks
	References
Chapter 16: Therapeutic Potential
	16.1 Examples of Metastatic Tumors
	16.2 Malignant Melanoma as a Model of Anticancer Therapy
		16.2.1 Clinical Statistics
	16.3 Immune Checkpoint
	16.4 Metastatic Trait of Tumor Cells Per se
	16.5 Triangle-Based Idea to Treat Tumors
		16.5.1 Target Angiogenesis
			16.5.1.1 VEGFR1
			16.5.1.2 PlGF
			16.5.1.3 PHD2
			16.5.1.4 Sema3A
		16.5.2 Target Coagulation
			16.5.2.1 Fibrinogen
			16.5.2.2 16 K PRL
			16.5.2.3 Warfarin-TAM Receptor
		16.5.3 Target Inflammation
			16.5.3.1 Lipid Mediators (see Sect. 1.4.5 for Biochemistry)
				16.5.3.1.1 PGE2
				16.5.3.1.2 Resolvin E (RvE) and RvD
			16.5.3.2 Steroid
			16.5.3.3 The Issue of TNF
			16.5.3.4 CXCL12
			16.5.3.5 CCL3 Causes the Abscopal Effect
			16.5.3.6 SAA
			16.5.3.7 S100A8 and S100A9
				16.5.3.7.1 Overview
				16.5.3.7.2 Small Molecules
				16.5.3.7.3 Peptibodies
				16.5.3.7.4 TLR4 Antagonists
			16.5.3.8 How to Think of HMGB1 Binding to CXCL12
			16.5.3.9 S100A8/A9-AA Binds CD36
			16.5.3.10 S100A9 Binds CD147 (EMMPRIN)
			16.5.3.11 CCL2-CCR2 Signaling Block
			16.5.3.12 CXCL1-S100A8 Loop
				16.5.3.12.1 Double-Edged Swords
			16.5.3.13 S1P
			16.5.3.14 PPARγ Agonists
			16.5.3.15 Tyrosine Kinase Inhibitor
				16.5.3.15.1 Met Inhibitors
				16.5.3.15.2 Jak2
				16.5.3.15.3 Syk
				16.5.3.15.4 ABL
			16.5.3.16 mTOR Inhibitors
			16.5.3.17 Targeting microRNA
			16.5.3.18 CRP
			16.5.3.19 Miscellaneous Targets
				16.5.3.19.1 HDAC
				16.5.3.19.2 SNS Blocker
				16.5.3.19.3 Midkine
				16.5.3.19.4 Osteopontin
	16.6 Concluding Remarks
	References