Tumor Stroma: Biology and Therapeutics

Cover
Half Title
Title Page
Copyright Page
Dedication
Table of Contents
Preface
Chapter 1: The Tumor Stroma: Key Component of Solid Tumors
	1.1: Normal Stroma Versus Tumor Stroma
	1.2: Cellular Composition of the Tumor Stroma and Its Interactions
	1.3: Non-cellular Composition of the Tumor Stroma and Its Interactions
	1.4: Tumor Stroma Architecture and Heterogeneity
	1.5: Pathological Significance of the Tumor Stroma
	1.6: Therapeutic Opportunities in the Tumor Stroma
Chapter 2: Cancer-Associated Fibroblasts: Building Blocks of the Tumor Stroma
	2.1: Cancer-Associated Fibroblasts
	2.2: Molecular Characteristics of CAFs
		2.2.1: Transcriptomic Regulation
		2.2.2: Epigenetic Regulation
	2.3: Origin and Heterogeneity of CAFs
		2.3.1: CAFs in Breast Cancer
		2.3.2: CAFs in Lung Cancer
		2.3.3: CAFs in Pancreatic Cancer
	2.4: Functions of CAFs in Cancer
		2.4.1: Role of CAFs in Cancer Progression
		2.4.2: Role of CAFs in Cancer Metastasis
		2.4.3: Role of CAFs in Chemoresistance
		2.4.4: Role of CAFs in Building Stroma and ECM Remodeling
		2.4.5: Role of CAFs in Tumor Metabolism
		2.4.6: Role of CAFs in Inducing Immunosuppression
	2.5: Therapeutic Strategies Against CAFs
		2.5.1: Depletion of CAFs
		2.5.2: Intervening into CAF Activation
			2.5.2.1: Inhibition of TGF-β signaling
			2.5.2.2: Inhibition of Hedgehog signaling
			2.5.2.3: Inhibition of PDGF signaling
			2.5.2.4: Inhibition of JAK/STAT signaling
		2.5.3: Reprogramming of CAFs
			2.5.3.1: Vitamin D3 receptor agonists
			2.5.3.2: CTGF inhibition
			2.5.3.3: Integrin inhibitors
		2.5.4: Interference with Metabolic Reprogramming of CAFs
	2.6: Conclusions and Future Outlook
Chapter 3: Tumor-Associated Macrophages: Biological Understanding and Therapeutic Opportunities
	3.1: Cancer
	3.2: Complex Tumor Microenvironment
		3.2.1: Dendritic Cells
		3.2.2: Myeloid-Derived Suppressor Cells
		3.2.3: Neutrophils
		3.2.4: T Cells
	3.3: Tumor-Associated Macrophages
		3.3.1: Macrophage Development
		3.3.2: Macrophage Heterogeneity
		3.3.3: Significance and Roles of TAMs in Cancer
			3.3.3.1: TAM roles in tumor growth
			3.3.3.2: TAM roles in angiogenesis and invasion/metastasis
			3.3.3.3: TAM roles in the immunosuppressive phenotype of TME
	3.4: TAM-Targeted Therapy
		3.4.1: Interference with TAM Survival
		3.4.2: Inhibition of TAM Recruitment
		3.4.3: Repolarization of Protumor TAM into Antitumor TAMs
	3.5: Conclusion and Future Perspectives
Chapter 4: Biomarkers in the Tumor Stroma and Their Clinical Relevance
	4.1: Introduction
	4.2: Importance of Biomarkers in Cancer Diagnosis and Prognosis
	4.3: Stromal Biomarkers in Cancers
	4.4: Tumor Stroma Evolution
	4.5: Composition of the Tumor Stroma and Its Role in Tumor Development, Progression, and Metastasis
	4.6: Cancer-Associated Fibroblasts and Biomarkers
		4.6.1: Crosstalk of Carcinoma-Associated Fibroblasts in the Tumor Stroma
		4.6.2: CAF Heterogeneity and Role in Tumor Evolution
		4.6.3: CAF Biomarkers and Clinical Relevance
	4.7: Extracellular Matrix and Biomarkers
		4.7.1: Collagens
		4.7.2: Proteoglycans
		4.7.3: Laminins
		4.7.4: Role of ECM in EMT
	4.8: ECM Biomarkers and Clinical Relevance
	4.9: Matrix Metalloproteinases as Biomarkers
	4.10: Immune Cells and Biomarkers
	4.11: Stromal Serum Biomarkers
	4.12: Physical Features of the Tumor Stroma and Relevance as Biomarkers
		4.12.1: Intra-tumoral Pressure as a Biomarker
	4.13: Clinical Importance of the Tumor Stromal Biomarkers and Future Implications
	4.14: Conclusion
Chapter 5: Physical Properties of the Tumor Stroma and Therapeutic Strategies
	5.1: Introduction
	5.2: Mechanical Stiffness and Solid Stress
		5.2.1: Tissue Stiffness
		5.2.2: Solid Stress
			5.2.2.1: Relation between tissue stiffness and solid stress
	5.3: Changes in the Interstitial Fluid Pressure
	5.4: Hypoxic Conditions in the Tumor Stroma
	5.5: Therapeutic Approaches to Modulate Physical Properties of the Tumor Stroma
		5.5.1: Therapeutic Strategies to Target CAFs
		5.5.2: Reduction of Stress in the Tumor Stroma Using Anti-hypertensive Agents
		5.5.3: Degradation of ECM
		5.5.4: Vascular Normalization
		5.5.5: Hypoxia Alleviation
	5.6: Summary and Future Challenges
Chapter 6: TGF-β Signalling in Cancer: Role and Therapeutic Targeting of the Tumour Stroma
	6.1: Introduction
		6.1.1: Cancer Development: Subversion of Physiological Processes
		6.1.2: Oncogenes and Tumour Suppressors
		6.1.3: Looking Beyond Cancer Cells
	6.2: TGF-β’s Role on Carcinogenesis
		6.2.1: TGF-β Secretion and Activation
		6.2.2: TGF-β Signalling Pathway
		6.2.3: TGF-β: Tumour Suppressor and Tumour Promoter
	6.3: TGF-β Mediates the Intricate Crosstalk in the Tumour Stroma
		6.3.1: TGF-β Inhibition of Adipocyte Differentiation and Adipogenesis
		6.3.2: Angiogenesis and Vascular Integrity Regulated by TGF-β
		6.3.3: TGF-β-Induced Immunosuppression
		6.3.4: Activation of CAFs by TGF-β
	6.4: Anti-TGF-β Therapies in Cancer
		6.4.1: Pharmacological and Genetic Disruption of TGF-β Signalling
		6.4.2: TGF-β Pharmacological Inhibitors Targeting the Tumour Stroma
	6.5: Conclusions and Future Perspectives
Chapter 7: Role of Integrins in the Tumor Stroma
	7.1: Introduction
	7.2: Molecular Biology of Integrins
		7.2.1: α and β Subunits
		7.2.2: Functions
		7.2.3: Signaling Pathways of Integrin Receptors
		7.2.4: Integrin Receptors’ Interactions
		7.2.5: Interaction of Integrins with Growth Factor Receptors
			7.2.5.1: Interaction with VEGFR
			7.2.5.2: Interaction with TGFR-β
			7.2.5.3: Interaction with FGFR
			7.2.5.4: Interaction with PDGFR
	7.3: Role of Integrins in the Tumor Stroma
		7.3.1: Integrins in CAFs
		7.3.2: Integrins in Macrophages
		7.3.3: Integrins in Cancer Cells
		7.3.4: Integrins in Endothelial Cells
	7.4: Integrin-Based Therapeutics
		7.4.1: Antibody-Based Therapeutics
		7.4.2: Peptide-Based Therapeutics
		7.4.3: Integrins as Targeted Receptors
		7.4.4: Other Therapeutic Strategies
	7.5: Conclusions
Chapter 8: MicroRNA in the Tumor Stroma: Diagnostic and Therapeutic Implications
	8.1: Introduction
	8.2: MicroRNA in the Tumor Microenvironment
		8.2.1: Cancer-Associated Fibroblasts
		8.2.2: Tumor-Associated Macrophages and Immune Cells
		8.2.3: Tumor Vascular Cells
	8.3: MicroRNA in the Circulation and Other Body Fluids
		8.3.1: MicroRNA in Blood
		8.3.2: MicroRNA in Other Biological Fluids
	8.4: MicroRNA Delivery for Cancer Treatment
		8.4.1: Strategies for miRNA Delivery
		8.4.2: MicroRNA Delivery to the Tumor Stromal Cells
	8.5: Clinical Progress of miRNA-Targeted Therapy
	8.6: Conclusion
Chapter 9: Molecular Imaging of the Tumor Stroma and Beyond
	9.1: Introduction
	9.2: Tumor Vasculature
		9.2.1: Targeted Vascular Imaging
		9.2.2: Lymphatic Tumor Vasculature
		9.2.3: Functional (Non-targeted) Vascular Imaging
		9.2.4: Hypoxia
	9.3: Immune Cells
		9.3.1: T Cells
		9.3.2: Dendritic Cells
		9.3.3: Tumor-Associated Macrophages
	9.4: Cancer-Associated Fibroblasts
	9.5: Mesenchymal Stromal Cells
	9.6: Extracellular Matrix
		9.6.1: Collagen
		9.6.2: Laminins
		9.6.3: Fibronectin
		9.6.4: Hyaluronan (Hyaluronic Acid)
		9.6.5: Other Proteoglycans
	9.7: Matrix Metalloproteinases
		9.7.1: Hyaluronidase
		9.7.2: Transglutaminases
	9.8: Metabolic Imaging and Alternative Imaging Methods
		9.8.1: Glucose Metabolism
		9.8.2: Choline–Phospholipid Metabolism
		9.8.3: pH
	9.9: Future Perspectives
Chapter 10: 3D in vitro Models to Mimic the Tumor Microenvironment
	10.1: Introduction
	10.2: 2D in vitro Co-cultures and ex vivo Models
	10.3: Recent Developments in 3D in vitro Models of the Tumor Microenvironment
		10.3.1: Cell-Based Methodology
			10.3.1.1: Spheroid-based platforms
			10.3.1.2: Organoid-based platforms
			10.3.1.3: Intermediate summary on cell-based 3D in vitro models
		10.3.2: (Biomedical) Engineering-Based Methodology
			10.3.2.1: Scaffold-based platforms
			10.3.2.2: 3D bioprinting-based platforms
			10.3.2.3: Microfluidic-based platforms
			10.3.2.4: Vascularized platforms
		10.3.3: Intermediate Summary on Biomedically Engineered 3D in vitro Models
	10.4: 4D in vitro Models of the TME
	10.5: Computational Models of the TME
	10.6: Future Challenges and Outlook
Index