Tumor Microenvironment: Cellular, Metabolic and Immunologic Interactions (Advances in Experimental Medicine and Biology, 1350)

Over the past decade, the tumor microenvironment has become one of the most important research areas in cancer biology, as cells within the tumor microenvironment, despite being outnumbered by healthy cells, are able to evade surveillance and immune-mediated destruction. While researchers have learned a great deal about the cellular and structural makeup of the tumor microenvironment, there has been a growing understanding of the metabolic interplay between the tumor micronenvironment’s various cellular constituents and how each of them contributes to overall tumor growth and metastases. This new volume will guide researchers, students, oncologists and academics through a rapidly developing and changing field with a thorough understanding of tumor microenvironment biology from a cellular, structural, metabolic, and immunological perspective. Preface 6 References for general reading on history of Tumor Microenvironment: 10 Contents 11 About the Editors 12 Inflammatory Components of the Thyroid Cancer Microenvironment: An Avenue for Identification of Novel Biomarkers 13 1 Tumor Microenvironment of Solid Tumors 13 1.1 Defining the Tumor Microenvironment 13 1.2 Cellular Constituents of the Tumor Microenvironment 14 1.2.1 Cancer-Associated Fibroblasts (CAFs) 14 1.2.2 Endothelial Cells (ECs) 14 1.2.3 Cancer Stem Cells (CSCs) 15 1.2.4 Immune Cells 15 1.3 Immune Cells of the Tumor Microenvironment 15 1.3.1 Natural Killer Cells (NK Cells) 15 1.3.2 Dendritic Cells 15 1.3.3 Mast Cells 16 1.3.4 T Regulatory Cells (Tregs) 16 1.3.5 CD8+ Cytotoxic T Cells (CTLs) 16 1.3.6 Tumor-Associated Macrophages (TAMs) 18 2 Specificity of the Thyroid Tumor Microenvironment 19 2.1 Anatomy of the Thyroid Gland 19 2.2 Thyroid Cancer 19 2.3 Heterogeneity of Thyroid Cancer Cells 20 2.4 Anaplastic Thyroid Cancer 21 2.5 Amplified Metastatic Propensity of Anaplastic Thyroid Cancer 21 2.6 Thyroid Cancer and Inflammation 22 2.7 Dynamic Nature of the Thyroid Tumor Microenvironment 22 2.8 Immune Cell Remodeling of the Thyroid Tumor Microenvironment 23 2.9 Immune Surveillance in the Thyroid Tumor Microenvironment 25 2.10 Evolution of the Metastatic Phenotype Via Macrophages 25 2.11 Interacting Molecules of the Thyroid Tumor Microenvironment 26 2.11.1 Cytokines and Chemokines 26 2.11.2 Exosomes 27 3 Cellular Communication in the Tumor Microenvironment 30 4 Future Directions 31 4.1 Novel Targets of Therapeutic Intervention 31 References 36 Disruption of Cell-Cell Communication in Anaplastic Thyroid Cancer as an Immunotherapeutic Opportunity 44 1 Tumor Microenvironment 44 2 Cellular Constituents 45 2.1 Immune Cells 45 2.1.1 Macrophages 45 2.1.2 Dendritic Cells (DCs) 45 2.1.3 Natural Killer (NK) Cells 46 2.1.4 T Lymphocytes 47 2.2 Nonimmune Cells 47 2.2.1 Neuroendocrine Cells 47 2.2.2 Adipose Cells 48 2.2.3 Endothelial Cells 49 2.2.4 Mesenchymal Cells 50 2.2.5 Fibroblasts 50 3 Dynamic Nature of the Tumor Microenvironment 51 4 Specificity of the Thyroid Tumor Microenvironment 53 4.1 Immune Landscape in Anaplastic Thyroid Cancer 53 4.2 Immune Surveillance in Thyroid Cancer 54 4.3 Evolution of the Metastatic Phenotype 55 4.4 Interacting Molecules 58 4.4.1 ATC Has a Complex Cytokine Milieu 58 4.4.2 Immune Targets on the Tumor and Its Tripartite Cell-Cell Communication 59 4.4.3 T Cell Co-signaling Molecules 59 4.4.4 Immune Checkpoint Molecules in Cancer 59 4.4.5 ATC Has T Cell-Inflamed Immune Microenvironment 61 4.4.6 Immune Modulatory Molecules in ATC: An Unexplored Realm 61 5 Consequences of Three-Way Communication 62 5.1 Inflammation and Immune Checkpoint Molecules: A Complex Interplay 63 6 HVEM/CD160/BTLA Axis in ATC 63 6.1 Novel Targets of Therapeutic Intervention 64 7 HVLA/BTEM Axis as Potential Therapeutic Target 64 8 Importance of TME Interacting Components Targets 68 9 Further Studies in ATC: Cytokines, miRNAs, Exosomes, etc. 68 References 70 Exosomes in the Healthy and Malignant Bone Marrow Microenvironment 78 1 The Bone Marrow Microenvironment 78 1.1 Endosteal Niche 79 1.2 Perivascular Niche 79 2 Exosomes 79 2.1 Characterization 79 2.2 Biogenesis 80 2.3 Cargo 80 2.4 Docking and Release 81 2.5 Uptake and Downstream Effects 81 3 Bone Marrow-Associated Cancers 82 4 Microenvironment in Maintaining Cancer Stem Cells 83 5 Exosome-Mediated Communication: Hematologic Malignancies 83 5.1 Endothelial Cells 83 5.2 Mesenchymal Stem Cells (MSCs) 84 5.3 Macrophages 85 5.4 Osteoblasts 85 6 Exosome-Mediated Communication: Bone Marrow-Metastatic Breast Cancer 85 6.1 Endothelial Cells 85 6.2 Mesenchymal Stem Cells 85 6.3 Macrophages 86 6.4 Osteoblasts 86 7 Therapeutic Strategies 87 7.1 Current Therapies 87 7.2 Exosome-Based Therapies 87 7.3 Limitations of Exosome-Based Therapies 88 7.4 3D BMM: In Vitro Approaches to Improve Clinical Efficacy 89 8 Conclusion 90 References 90 Structural Biology of the Tumor Microenvironment 101 1 Structural Biology of the TME 101 2 Cellular Elements 101 2.1 Fibroblasts 101 2.2 Adipocytes 102 2.3 Vascular Endothelial Cells 102 2.4 Pericytes 102 2.5 Lymphatic Endothelial Cells 102 2.6 Immune Cells 103 3 Structural Elements 104 3.1 Vasculature 104 3.2 Extracellular Matrix 104 3.3 ECM Structural Proteins 105 References 106 Metabolic Interactions Between Tumor and Stromal Cells in the Tumor Microenvironment 111 1 Introduction 111 2 Metabolic Alterations in Cancer Cells 112 3 Signaling Pathways Promoting Metabolic Alterations in Tumor 113 4 Signaling Pathway Alterations in Tumor-Associated Stroma 114 5 Stromal Heterogeneity in the Tumor Microenvironment 115 6 CAFs as Mediators of Tumor-Stroma Interaction 117 7 Chemokines in Driving Tumor-Stroma Interactions 118 8 Lactate in Driving Tumor-Stroma Interactions 120 9 Epigenetic Reprogramming in the Tumor Microenvironment 121 10 Therapeutic Targeting of Molecular Interaction Between Tumor and Stroma 124 11 Conclusion 126 References 126 Interacting Genetic Lesions of Melanoma in the Tumor Microenvironment: Defining a Viable Therapy 132 1 Types of Melanoma 132 2 Therapeutic Options 132 3 Genetic Lesions and Immunogenicity in Melanoma 133 4 The Melanoma Tumor Microenvironment 134 4.1 Immunoglobulin Superfamily 137 4.2 Tumor Necrosis Factor Receptor Superfamily 137 5 Expression of Immune Targets on Melanoma Cells 138 6 Perspectives 144 7 HVEM/BTLA/CD160 Interactome 147 References 148 Noncoding RNAs in Papillary Thyroid Cancer: Interaction with Cancer-Associated Fibroblasts (CAFs) in the Tumor Microenvironment (TME) and Regulators of Differentiation and Lymph Node Metastasis 153 1 Introduction 153 1.1 Overview of the Thyroid Gland 153 1.1.1 Normal Thyroid Differentiation and Thyroid Hormone Synthesis 153 1.1.2 Thyroid Hormone Production and Regulation 154 1.2 Papillary Thyroid Carcinoma 154 1.2.1 Classification of Thyroid Cancers 154 1.3 Diagnostic and Therapeutic Approach to Thyroid Nodules 154 1.3.1 Initial Evaluation of a Thyroid Nodule 154 1.3.2 FNA and Current Molecular Classifiers 155 1.3.3 Treatment Modalities 155 1.3.4 Potential Role of Novel Biomarkers 155 1.4 lncRNAs in Papillary Thyroid Cancer 156 1.4.1 Structure and Function of lncRNAs 156 1.4.2 lncRNA Investigation in Papillary Thyroid Cancer 156 2 lncRNAs Highly Associated with Thyroid Differentiation and Tissue-Specific Expression 157 3 lncRNAs Expressed in Primary Tumors that Predict LNM 158 4 lncRNas as Regulators of Molecular Phenotype and Interaction with Components of TME 159 References 160 Index 164