Tumor Microenvironment: Novel Concepts (Advances in Experimental Medicine and Biology, 1329)

Preface
Contents
About the Editor
The Tumour Microenvironment and Circulating Tumour Cells: A Partnership Driving Metastasis and Glycan-Based Opportunities for Cancer Control
	1 Introduction
	2 Tumour Microenvironment Promotion of EMT and Tumour Invasion
	3 Tumour Microenvironment Promotion of Haematogenous Metastasis
	4 Tumour Microenvironment Promotion of CTC Colonization
		4.1 Tumour-Secreted Soluble Factors
		4.2 Tumour-Derived Exosomes
	5 Adaptation of CTC to Foreign Site Microenvironments
	6 Glycosylation: A Key Post-translational Modification Driving Metastasis and Its Potential for Targeted Therapeutics
	7 Concluding Remarks
	8 Ongoing Challenges and Future Perspectives
	References
Dormancy in the Tumor Microenvironment
	1 Introduction
	2 Osteogenic and Stem Cell–Driven Dormancy
	3 Vascular/Angiogenic Dormancy
	4 Hypoxia
	5 Immunologic Dormancy
	6 Conclusion
	References
Tumor-Associated Tertiary Lymphoid Structures: A Cancer Biomarker and a Target for Next-generation Immunotherapy
	1 Introduction
	2 TLS Versus SLO: Which Came First in Animal Evolution?
	3 TLS and SLO: Is There Redundancy in the Immune System?
	4 TLS: a Powerful Prognostic Biomarker in Cancers
		4.1 Prognostic Factor Across Human Cancer Types
		4.2 Methods for TLS Quantification
	5 TLS: A Key Target for Next-generation Immunotherapy
	6 Conclusion and Perspectives
	References
Studying the Tumor Microenvironment in Zebrafish
	1 Introduction
	2 Innate Immune Cells in the Zebrafish TME
		2.1 Recruitment and Pro-tumor Functions
			2.1.1 Neutrophils and Macrophages
			2.1.2 Microglia/Macrophages
		2.2 The Role of Innate Immune Cells in Metastasis
			2.2.1 Neutrophils
			2.2.2 Macrophages
			2.2.3 Endothelial Cells, Extravasation, and Proliferation at the Metastatic Site
	3 A Role of Adipocytes in Tumor Growth and Invasion
	4 Fibroblasts
	5 Neo-angiogenesis
	6 Future Directions
	References
Pre-metastatic Niche Formation by Neutrophils in Different Organs
	1 Introduction
	2 Neutrophil Development
	3 Emergency Granulopoiesis
	4 Neutrophils in Cancer
	5 Metastasis and Metastatic Seeding
	6 Pre-metastatic Niche
	7 Recruitment of Neutrophils into Pre-metastatic Organs
	8 The Influence of Neutrophils on the Formation of Pre-metastatic Niche
		8.1 Inflammation as a Stimulus for Metastasis
		8.2 Deregulation of Adaptive Immune Responses
		8.3 Direct Support of Tumor Cell Growth by Neutrophils
		8.4 Released Neutrophil Factors Support Tumor Survival
		8.5 NETosis as Pro-metastatic Factor
	9 Summary and Future Perspectives
	References
Tumor Cell Invasion and the Tumor Microenvironment: Special Focus on Brain Tumors
	1 Introduction
	2 General Features of the Invasive Process in Glioblastoma
	3 Invasive Mechanisms at the Level of Tumor Cells
	4 Brain Tumor Blood Vessels, Vessel Co-option, and Invasion
	5 Immune System and Tumor Cell Invasion
	6 Invasion of White Matter Tracts by Glioma Cells
	7 Role of Tumor-Associated Astrocytes in Glioblastoma Invasion
	8 Role of the Extracellular Matrix in Tumor Invasion
	9 Conclusion
	References
The Dog as a Model to Study the Tumor Microenvironment
	1 Introduction
	2 Components of Tumor Microenvironment
	3 A Special Insight on the Role of Macrophages and T-Lymphocytes in Tumor Microenvironment
		3.1 Macrophage, The Head of the Orchestra
			3.1.1 Macrophages and Tumor Initiation: A Crosstalk with a Chronic Inflammation State
			3.1.2 Macrophages and Tumor Metastasization
			3.1.3 Macrophages as Therapeutic Targets in Cancer
		3.2 T-Lymphocytes in the Tumor Microenvironment
			3.2.1 T-Lymphocytes and Tumor Initiation
			3.2.2 T-Lymphocytes and Tumor Metastization
			3.2.3 Lymphocytes as Therapeutic Targets in Cancer
		3.3 Lactate Efflux and the Interaction with T-Lymphocytes and Macrophages in Tumor Microenvironment: A Dance with the “Wolfs”
			3.3.1 Cancer Progression and Immunologic Escape
			3.3.2 Lactic Acid and Tumor Metastasization
	4 Concluding Remarks
	References
Efferocytosis and the Story of “Find Me,” “Eat Me,” and “Don’t Eat Me” Signaling in the Tumor Microenvironment
	1 Introduction
	2 Cellular Mechanism of Efferocytosis
	3 Tumor Survival and Metastasis Need Efferocytosis
	4 Conclusion and Future Perspectives
	References
Color-Coded Imaging of the Tumor Microenvironment (TME) in Human Patient–Derived Orthotopic Xenograft (PDOX) Mouse Models
	1 Introduction
	2 Materials and Methods
		2.1 Mice
		2.2 Animal Care
		2.3 Establishment of a PDOX Model of Patient Tumors
		2.4 Patient-Derived Orthotopic Xenograft (PDOX) Transgenic Fluorescent Protein–Expressing Nude Mouse Models
		2.5 Establishment of a PDOX Model of Soft Tissue Sarcoma
		2.6 Fluorescence Imaging
		2.7 Confocal Microscopy
		2.8 Histological Analysis
		2.9 GFP-Expressing Telomerase-Specific Adenovirus
		2.10 OBP-401-GFP Labeling of an RFP-Expressing PDOX
	3 Results and Discussion
		3.1 GFP Host Stromal Cells Infiltrate a Pancreatic Cancer PDOX
		3.2 GFP Host Stromal Cells Infiltrate Peritoneal-Disseminated Metastases of Pancreatic Cancer PDOX
		3.3 RFP Host Stromal Cells Infiltrate Pancreatic Cancer PDOX
		3.4 GFP Host Stromal Cells Infiltrate Pancreatic PDOX Labeled with RFP Stroma to Form a Two-Color Stroma Model
		3.5 CFP Host Stromal Cells Infiltrate Pancreatic Cancer PDOX Previously Grown in RFP and GFP Transgenic Mice to Form a Three-Color Stroma Model
		3.6 OBP-401-GFP Labeling of Cancer Cells in Pancreatic Cancer PDOX with RFP-Expressing Stroma
		3.7 Color-Coded Imaging to Visualize Selective Stromal Cell Therapy
		3.8 Noninvasive Imaging of a PDOX Sarcoma in Noncolored Nude Mouse After a Single Passage in RFP Nude Mouse
		3.9 Imaging of Body Imaging and the RFP Stroma in the UPS Imageable PDOX (iPDOX) Model During Multiple Passages
	4 Conclusion
	References
Mitochondria and the Tumour Microenvironment in Blood Cancer
	1 Introduction
	2 The Bone Marrow
	3 Haematopoiesis
	4 Bone Marrow Microenvironment
		4.1 HSC Niche
		4.2 Cell Compartments of the BM Microenvironment
		4.3 BMSC and Normal Haematopoiesis
	5 Aging and Tumour Microenvironment of the BM
		5.1 Aging
		5.2 Blood Cancer
		5.3 Multiple Myeloma
		5.4 Acute Lymphoblastic Leukaemia
		5.5 Acute Myeloid Leukaemia
	6 Mitochondria and Mitochondrial Transfer to Malignant Blood Cells
		6.1 Mitochondria
		6.2 Mitochondrial Transfer
		6.3 Tunnelling Nanotubules
		6.4 Extracellular Vesicles
		6.5 Gap Junctions
	7 Mitochondrial Transfer and Microenvironment in Solid Tumours
	8 Conclusions
	References
Telocytes in the Tumor Microenvironment
	1 Introduction
	2 The Nature of Telocytes
	3 Tumor Angiogenesis
	4 Telocytes and Signaling Molecules
	5 Telocytes and Immune Cells
	6 Telocytes and Fibroblasts
	7 The Role of Telocytes in the Production of Extracellular Matrix
	8 Conclusions and Future Directions
	References
Modeling the Roles of Astrocytes in the Metastatic Tumor Cell Microenvironment
	1 Introduction
	2 Two-Dimensional (2D) Models
		2.1 2D Single-Cell Assays
		2.2 2D Scratch Assay
		2.3 Two-Dimensional Coculture Assay
	3 Three-Dimensional (3D) Models
		3.1 Transwell Insert Models (Boyden Chambers)
		3.2 Spheroid Culture
	4 Effect of Astrocytes on Endothelial Cells
	5 In Vivo Models
	6 Human Samples
	7 Microfluidic Models
	8 Conclusion and Outlook
	References
Roles of Fibroblasts in Microenvironment Formation Associated with Radiation-Induced Cancer
	1 Introduction
	2 Fibroblasts in Tumor Microenvironment
	3 Effects of Radiation on Human Health
	4 Radiation-Induced Cancer
	5 Mitochondria as a Biological Radiation Target
	6 Roles of ATM in Mitochondrial Radiation Response
	7 Oxidative Stress and Cancer
	8 Tumor Microenvironment in Radiation-Related Cancer
	References
Tumor Microenvironment–Associated Pericyte Populations May Impact Therapeutic Response in Thyroid Cancer
	1 Introduction
	2 Ontogeny and Lineage of Pericytes
	3 Biology of Pericytes
	4 Pericyte and Normal Thyroid Function
	5 Thyroid Cancer Microenvironment
	6 Role of Pericytes in Tumor Metastasis
	7 Role of Pericyte in Drug Resistance
	8 Targeting Pathways That Are Functional in Pericytes
	9 Conclusions
	References
The Adrenergic Nerve Network in Cancer
	1 Introduction
	2 Main Text
		2.1 Adrenergic Nerve Signaling Bridges the Brain and Peripheral Tumors
		2.2 Adrenergic Axonogenesis and Neurogenesis in the Tumor Microenvironment
		2.3 Adrenergic Signaling and Crosstalk in Tumors
			2.3.1 Adrenergic Signaling and Crosstalk with Cancer Cells
			2.3.2 Adrenergic Signaling and Crosstalk with the TME
				Immune Cells
				Endothelial Cells
				Lymphatic Cells
				Mesenchymal Stem Cells, Cancer-Associated Fibroblasts, and Adipocytes
		2.4 Adrenergic Signaling and Therapies
	3 Commentary
	References
Current Treatment Modalities Targeting Tumor Microenvironment in Castration-Resistant Prostate Cancer
	1 Introduction
		1.1 Tumor Microenvironment in Prostate Cancer Progression
		1.2 Secondary Hormonal Manipulations
		1.3 Chemotherapy in Metastatic CRPC
		1.4 Taxanes
		1.5 Targeting Immune Checkpoint Inhibitors
		1.6 Targeting Inhibitors of Steroidogenic Enzymes
		1.7 Tyrosine Kinase Inhibitors
	2 Treatment Modalities for CRPC
		2.1 Non-metastatic CRPC (NM-CRPC)
		2.2 Asymptomatic Metastatic CRPC (mCRPC)
		2.3 Symptomatic Metastatic CRPC
		2.4 Non-standardized Therapies for Symptomatic Metastatic CRPC
		2.5 Immunotherapy Targeting TME
	3 Limitations of Current Trials
	4 Conclusion
	References
Brain Metastases and Microenvironment
	1 Introduction
	2 Brain Metastases
		2.1 Features and Challenges
		2.2 Metastatic Cascade
	3 Microenvironment
		3.1 Tumor Microenvironment and the Pre-metastatic Niche
		3.2 Extracellular Matrix
		3.3 Cancer Cells
		3.4 Immune Cells
		3.5 Astrocytes
		3.6 Neurons
		3.7 Endothelial Cells
		3.8 Pericytes
	4 Future Trends
	References
Migration Stimulating Factor (MSF): Its Role in the Tumour Microenvironment
	1 Introduction
		1.1 Background: Initial Identification of MSF
		1.2 Molecular Structure of MSF: Function-Neutralising and Identification Antibodies
		1.3 MSF Expression: Diagnostic and Prognostic Relevance
		1.4 MSF Bioactivities, Modulation and Mode of Action
		1.5 Conclusions and Future Work
	2 Background: Initial Identification of MSF
		2.1 Relevance of the Extracellular Matrix Used in Migration Assays
		2.2 Distinct Fibroblast Migratory Phenotypes
	3 Molecular Structure of MSF: Function-Neutralising and Identification Antibodies
		3.1 The Structure of MSF: Comparison with Fibronectin
		3.2 Antibodies Used to Identify and Characterise MSF Proteins
	4 MSF Expression: Diagnostic and Prognostic Relevance
		4.1 Presence of MSF and MSF Inhibitors in Tissue Culture
		4.2 Modulation of MSF Expression
		4.3 Presence of MSF in Tissues Ex Vivo: Diagnostic and Prognostic Value
	5 MSF Bioactivities, Modulation and Mode of Action
		5.1 Motogenic Activity: Permissive and Non-permissive Matrices
		5.2 Lack of Mitogenic Activity While Promoting Tumour Growth
		5.3 Bioactive Motifs in MSF
		5.4 Cell Heterogeneity Regarding MSF Bioactive Motifs
		5.5 Motogenic Activity of MSF Isoforms: Interactions with MSFIs
		5.6 Evidence of Distinct MSF Isoforms Present in Serum and Tumour Cell Lines
		5.7 Angiogenic Activity
		5.8 Integrin Binding and Downstream Signalling
		5.9 Remodelling the Microenvironment
	6 Conclusions and Future Work
		6.1 Cell Motility and MSF Autoactivation
		6.2 Systemic Expression of MSF: Relevance to Tumour Development
		6.3 Expression of MSF Isoforms and Modulators in Development and in Tumours: Interactions and Value as Tumour Biomarkers
		6.4 MSF Bioactivities and Possible Target for Antitumour Therapy
	References
Mechanical Signaling in the Mammary Microenvironment: From Homeostasis to Cancer
	1 Introduction
	2 Mechanical Signaling in Mammary Development and Homeostasis
		2.1 Embryogenesis
		2.2 Branching Morphogenesis and Homeostasis
		2.3 Lactation and Involution
		2.4 Perspectives on Mammary Mechanobiology
	3 Mechanical Forces in Breast Cancer
		3.1 Mechanical Forces and Signaling in Primary Breast Tumors
		3.2 Mechanical Forces and Signaling in Breast Cancer Metastasis
	4 Opportunities for Therapeutic Intervention
	5 Conclusions
	References
Osteopontin Signaling in Shaping Tumor Microenvironment Conducive to Malignant Progression
	1 Introduction
	2 Structure and Functions of OPN
	3 OPN Receptors: CD44 and Integrins
	4 Role of OPN Signaling in Stroma-Tumor Interaction
		4.1 Role of OPN Signaling During Crosstalk Between CAFs and Cancer Cells
		4.2 OPN Signaling in MSC and Cancer Cell Crosstalk
		4.3 OPN Signaling in TAM and Cancer Cell Crosstalk
		4.4 OPN Signaling in Activation and Differentiation of T Cell Subsets in Cancer
		4.5 OPN Signaling in Tumor Vasculature: Crosstalk with Endothelial Cells
		4.6 Other Stromal Components of Tumor Microenvironment in Tumor Progression
	5 OPN Signaling and Hypoxic Response
	6 OPN Signaling and CSCs
	7 OPN Signaling in ECM Remodeling
	8 OPN and Cancer Metabolism
	9 Targeting OPN in the Tumor Microenvironment
	10 Future Prospective
	References
Progesterone Receptor Signaling in the Breast Tumor Microenvironment
	1 Overview
	2 Progesterone Receptor (PR) Structure and Function
		2.1 PR Classical Nuclear Signaling
		2.2 PR Extranuclear Signaling
	3 Progesterone and PR in Mammary Gland Development
		3.1 Role of PR and PR Isoforms in Mammary Gland Development
		3.2 Progesterone’s Role in Stem/Progenitor Cells in the Breast
	4 Paracrine Effects of Progesterone in Mammary Gland Development
		4.1 Paracrine Signaling by Progesterone
			4.1.1 Progesterone/PR and RANKL Signaling Pathways in Mammary Gland Development and Breast Cancer
				The Progesterone-Driven RANKL Pathway in the Breast
				The Progesterone-Driven RANKL Pathway in Breast Cancer Development
				Progesterone-RANKL Extracellular Signaling in Metastasis of Breast Cancer to Bones
			4.1.2 Progesterone/PR and Wnt Signaling Pathway in Mammary Gland Development and Breast Cancer
	5 Role of Progesterone and PR in the Breast Tumor Microenvironment
	6 ER/PR Cross-Communication and the Breast Tumor Microenvironment
	7 Summary and Future Directions
	References
Progranulin/GP88, A Complex and Multifaceted Player of Tumor Growth by Direct Action and via the Tumor Microenvironment
	1 Introduction
	2 Deconstructing and Reconstructing Tumor Development and Progression Complex Processes via the Establishment of Experimental Cell Culture Models
	3 Purification and Identification of Progranulin/GP88 as an Autocrine Growth Factor for a Highly Tumorigenic Cell Line
		3.1 Model System of Increased Tumorigenicity
		3.2 Purification of PCDGF the Autocrine Growth Factor Produced by PC Cells
		3.3 The 88 kDa Glycoprotein Is Not an Inactive Precursor but a Fully Biologically Active Molecular Entity
	4 Autocrine Stimulation of Proliferation of Cancer Cells by PGRN/GP88
	5 Autocrine Stimulation of Survival as a Mechanism for Chemoresistance Caused by PGRN/GP88
	6 Effect of PGRN/GP88 on Processes Contributing to Enhanced Metastasis
	7 Progranulin and the Tumor Microenvironment
		7.1 Interaction with Extracellular Matrix Proteins and Cytoskeletal Proteins
		7.2 Progranulin Involvement in the Tumor Microenvironment as a Major Contributor to Cancer Progression
	8 Prognostic Significance of Tissue and Secreted PGRN for Several Cancer Types
	9 Conclusion and Future Perspectives
	References
Sex-Based Differences in the Tumor Microenvironment
	1 Introduction
	2 Cancer-Associated Fibroblasts and Sexual Dimorphism
	3 Extracellular Matrix and Sexual Dimorphism
	4 Angiogenesis and Sexual Dimorphism
	5 Lymphangiogenesis and Sexual Dimorphism
	6 Immunity, Inflammation, and Sexual Dimorphism
		6.1 Macrophages
		6.2 NK and Antigen-Presenting Cells
		6.3 Neutrophils
		6.4 Lymphocytes T and B
		6.5 T Regulator Lymphocytes
	7 General Conclusions
	References
Index