The Extracellular Matrix and the Tumor Microenvironment (Biology of Extracellular Matrix, 11)

This book introduces the most important and best studied extracellular and pericellular molecules of the tumor microenvironment. It gives a comprehensive overview of their role in tumor development and cancer progression. Twelve chapters deal with the biochemical and biophysical background of extracellular matrix (ECM) changes in the tumor stroma compared to the physiological state. The reader learns about the major ECM components that are deregulated during cancer development and how they are associated with cancer progression associated with survival, inflammation process, among others. These are followed by recent data about the cooperative activity of extracellular matrix in tumor metabolism, promoting cancer progression. Two chapters focus specifically on the critical role of the ECM in tumor angiogenesis, linking this process to cellular infiltration and metastatic behavior of tumors. The final part describes how the ECM influences the success of immuno- and chemotherapy in cancer patients, its potential as biomarkers for diagnosis, prognosis, and therapeutic target, as well as the mechanism of resistance-associated changes in the ECM. This book is an interesting read for anyone who want to know more about ECM and cancer biology. Early career scientists can use it as an introduction to the field, offering an excellent tool for studying ECM. Advanced researchers and clinicians can gain a broader overview of the subject, considering the role of ECM for influencing every cancer hallmark as well as in the response of cancer treatments. The work serves to inspire future research and shows that the ECM should be considered as an important factor in the development of cancer therapeutics. The series "Biology of Extracellular Matrix" is published in collaboration with the American Society for Matrix Biology and the International Society for Matrix Biology. Preface Acknowledgement Contents Chapter 1: Small Leucine-Rich Proteoglycans Regulate Cancer Cell Growth, Apoptosis, and Associated Inflammation 1.1 Introduction on Cancer and Its Microenvironment 1.2 SLRPS Structure and Function-Focus on Biglycan and Lumican 1.2.1 Biglycan and Lumican Structure 1.3 Lumican and Biglycan Expression in Cancer and Correlation to Carcinogenesis 1.3.1 Biglycan and Lumican Affect Tumor Growth 1.3.2 Effects of Biglycan and Lumican on Cancer Cell Motility and Invasion 1.3.3 Biglycan and Lumican at the Crossroad between Apoptosis, Autophagy, and Cancer-Associated Inflammation 1.3.3.1 Effects on Apoptosis and Autophagy 1.4 Biglycan: A Regulator of Tumor-Associated Angiogenesis 1.5 Effects of Biglycan and Lumican on Chemoresistance 1.6 SLRPs as Cancer Therapy Targets 1.7 Conclusions References Chapter 2: The Role of Decorin in Cancer 2.1 Introduction 2.2 The Uprise of Decorin as an Antitumor Agent 2.2.1 Genetic Evidences 2.2.2 Decorin Expression in Cancers 2.2.3 Signaling in Cancers 2.2.3.1 Interaction with TGF-β and Other Growth Factors 2.2.3.2 Structural Components as Binding Partners 2.2.3.3 Decorin Acts as a pan-RTK Inhibitor 2.2.3.4 Intracellular Signaling Pathways 2.2.4 Inflammation, Immunomodulation 2.2.5 Autophagy, Mitophagy, and Angiogenesis 2.3 Therapeutic Applications 2.4 Conclusions References Chapter 3: The Mystery of Syndecan-1 in Tumor Development and Progression 3.1 Structure and Localization of Syndecans 3.2 Different Locations, Different Partners, Different Functions 3.3 Syndecan-1 and Signal Transduction 3.4 Syndecan-1 and Cancer; Does it Protect or Promote? 3.5 miR Regulation of Syndecan-1 Expression in Tumors 3.6 Syndecan-1 Is a Differentiation Marker with a Prognostic Value in Solid Tumors 3.7 Unpredicted Functions of Syndecan-1 in Tumors 3.8 Conclusion References Chapter 4: Syndecan-2 Biology and Its Role in Colorectal Carcinoma 4.1 Introduction 4.2 Structure and Glycosylation 4.3 Syndecan-2 Interactome and Signaling 4.4 Syndecan-2 in Human Diseases 4.5 Syndecan-2 in Colorectal Cancer 4.6 SDC2 Gene Methylation and Colon Cancer 4.7 Conclusions References Chapter 5: Versican in Tumor Progression, Tumor-Host Interactions, and Cancer Immunotherapy 5.1 VCAN: Structure and Variant Forms 5.2 VCAN Binding Partners in the Tumor Microenvironment 5.3 Post-Translational Modifications, Proteolysis, and VCAN-Matrikines 5.4 VCAN and VCAN-Matrikines in Development 5.5 VCAN in Tumor Progression and Metastasis 5.6 VCAN in Tumor Inflammation and Antitumor Immunity 5.7 VCAN Biomarkers in Tumor Immunology and Immunotherapy 5.8 Prospects for VCAN Therapeutics in the Immuno-Oncology Era References Chapter 6: Circulating Proteoglycans/Glycosaminoglycans as Cancer Biomarkers 6.1 Introduction 6.2 The Cellular Glycocalyx and Its Remodeling in Health and Disease 6.2.1 Cell Surface PGs 6.3 Circulating PGs/GAGs as Cancer Biomarkers 6.3.1 Hepatocellular Carcinoma 6.3.2 Multiple Myeloma 6.4 Conclusions References Chapter 7: Hyaluronan in the Extracellular Matrix of Hematological and Solid Tumors. Its Biological Effects 7.1 Introduction 7.1.1 HA and Tumor Progression 7.2 HA in Hematological Malignancy 7.2.1 HA and Leukemia 7.2.2 HA and Multiple Myeloma 7.2.3 HA and Lymphoma 7.3 Biological Effects of HA from ECM in Solid Tumors: Carcinomas, Sarcomas, and Gliomas 7.3.1 Carcinomas 7.3.1.1 HA and Breast Cancer 7.3.1.2 HA and Ovarian Cancer 7.3.1.3 HA and Prostate Cancer 7.3.1.4 HA and Pancreatic Cancer 7.3.1.5 HA and Colorectal Cancer 7.3.1.6 HA and Lung Cancer 7.3.2 HA and Sarcomas: Osteosarcoma, Chondrosarcoma, and Fibrosarcoma 7.3.3 HA and Glioblastoma 7.4 Conclusion and Perspectives References Chapter 8: Heparanase: A Paramount Enzyme for Cancer Initiation, Progression, and Metastasis 8.1 Introduction 8.2 Heparanase, Tumor Invasiveness, and Metastasis 8.3 Heparanase and Tumor Angiogenesis 8.4 Heparanase and Tumor Microenvironment 8.5 Heparanase, Autophagy, and Evading Cell Death 8.6 Heparanase in Inflammation 8.7 Heparanase, Exosome, and Chemoresistance 8.8 Concluding Remarks References Chapter 9: Laminins and Matrix Metalloproteinases Connection: A Subtle Relationship That Can Go Wrong in a Tumor Context, Part... 9.1 The Laminin Protein Family 9.2 Laminins as Multifunctional Elements Within Basement Membranes 9.3 Laminins Are Involved in the Regulation of MMP Expression and Activity 9.4 Laminins Are Cell Adhesion Ligands for CD44 9.5 Laminins Are Targets of MMPs Activity 9.6 Conclusion References Chapter 10: Basement Membrane, Collagen, and Fibronectin: Physical Interactions with Cancer Cells 10.1 The Biomechanical Role of ECM in Cancer Progression 10.2 2D Polystyrene Flask Cultures Partially Transformed in 3D Cultures Induce EMT in MCF-7 Breast Cancer Cells 10.3 MCF-7 Breast Cancer Cells in 2D and 3D Cultures (Millipore Filter, Concentrated Matrigel-Covered Millipore, Low Concentra... 10.4 MDA-MB-231 Breast Cancer Cells in 2D and 3D Cultures (Millipore Filter, Concentrated Matrigel-Covered Millipore, FN, Low ... 10.5 Migration Test and Real-Time PCR of MCF-7 and MDA-MB-231 Cells 10.6 Collagen as a Triggering Factor Inducing EMT in Breast Cancer Cells 10.7 LoVo-R Colon Cancer Cells in 2D Cultures and 3D Cultures (Matrigel-Covered Millipore, High Concentrated Type I Collagen-C... 10.8 Conclusions: Take Home Message References Chapter 11: Integrins in Cancer: Refocusing on the Tumor Microenvironment 11.1 Introduction 11.2 Tumor Fibrosis 11.2.1 CAFs in Desmoplastic TME 11.3 Pancreatic Cancer 11.3.1 CAF Heterogeneity in Pancreatic Cancer 11.3.2 Tumor Cell Integrins in Pancreatic Cancer 11.3.3 CAF Integrins in Pancreatic Cancer 11.3.4 CAF/Integrin-Mediated Chemoresistance in Pancreatic Cancer 11.4 Breast Cancer 11.4.1 CAF Heterogeneity in Breast Cancer 11.4.2 Tumor Cell Integrins in Breast Cancer 11.4.3 CAF Integrins in Breast Cancer 11.4.4 CAF-Mediated Chemoresistance in Breast Cancer 11.5 Lung Cancer 11.5.1 Lung Fibroblast Heterogeneity 11.5.2 Tumor Cell Integrins in Lung Cancer 11.5.3 CAF Integrins; The Role of Integrin α11β1 in Lung Cancer 11.5.4 Integrin-Mediated Chemoresistance in Lung Cancer 11.6 Conclusions References Chapter 12: Adipose Compounds in Breast Tumor Extracellular Matrix 12.1 Introduction 12.2 Breast Adipocytes 12.3 Clinical Association Between BCa and Obesity 12.4 CAAs and Crosstalk with BCa 12.4.1 Adipokines Produced by CAAs 12.4.1.1 Leptin 12.4.1.2 Adiponectin 12.4.1.3 Autotaxin and Resistin 12.4.1.4 Growth Factors HGF and IGF-1 12.4.1.5 Inflammatory Factors CCL2 and CCL5 Chemokines IL-6, IL-1(β) and TNF-α 12.4.1.6 Estrogens 12.4.1.7 microRNAs in AT and BCa Cells Crosstalk 12.5 Metabolic Reprogramming 12.6 Therapeutic Approaches Focused on BCa Cells and AT-Crosstalk 12.7 AT and Resistance in BCa Therapy 12.8 Concluding Remarks References Chapter 13: Extracellular Matrix as a Metabolic Niche in Cancer 13.1 Metabolic Rewiring and Altered Cellular Bioenergetics 13.2 Extracellular Matrix Elements Compensate Starving Conditions During Tumor Cell Growth and Survival in Tissue Microenviron... 13.3 The Effects of Lowering Glucose Concentration and High Lactate Level (Tissue Acidification) 13.3.1 Immunosuppressive Effects of Increased Lactate Level in the Extracellular Matrix 13.3.2 The Effects of Lactate in Metabolic Symbiosis (Including Several Functions of Fibroblasts and Endothelial Cells) 13.3.3 Direct Receptor-Ligand Signaling Effects of Lactate on Tumor Cells 13.3.4 Lactate Induces Tissue Remodeling 13.4 Other Altering Non-cellular Elements as Metabolic Factors in the Extracellular Matrix 13.5 Complex Metabolic Regulation in the Extracellular Matrix 13.6 Concluding Remarks References Chapter 14: The Role of Inflammatory Cells in Tumor Angiogenesis 14.1 Tumor Angiogenesis 14.2 Tumor Microenvironment 14.3 Pro-Angiogenic Factors 14.4 Angiogenic Inhibitors 14.5 TME Infiltrating Cells 14.6 TME Inflammatory Cells and Angiogenesis. Our Experience in the Study of Human Lymphomas 14.7 Targeting Angiogenesis and Inflammatory Cells in TME 14.8 Concluding Remarks References Chapter 15: Cancer Angiogenesis and Its Master Regulator Perlecan 15.1 Cancer Angiogenesis 15.2 Critical Participants of Tumor Angiogenesis 15.3 Structural Compartments of Tumor Blood Vessels 15.4 Regulatory Factors of Tumor Angiogenesis 15.4.1 Tumor-Associated Stromal Cells 15.4.2 Tumor-Associated Fibroblasts (TAFs) 15.4.3 Proangiogenic Factors 15.5 Natural Inhibitors of Angiogenesis 15.5.1 Proteolytic Breakdown Products 15.5.2 Noncoding RNAs 15.5.3 Heparin and Heparan Sulfate in the Regulation of Angiogenesis 15.5.4 Discovery and Structure of Perlecan 15.5.5 Perlecan Is an Indispensable Component of Basement Membranes 15.5.6 Physiological Functions of Perlecan 15.5.7 Perlecan in Pathology 15.5.8 Perlecan and Cancer 15.5.9 Perlecan and Tumor Angiogenesis 15.5.10 Endorepellin, the Angiostatic Fragment of Perlecan 15.5.11 Autophagy and Tumor Angiogenesis References Chapter 16: The microRNA-Extracellular Matrix Interplay in Breast Cancer 16.1 Introduction 16.2 ECM Regulates Breast Cancer Cell Progression Through miRNA Modulation 16.3 Conclusions and Perspectives References Chapter 17: The Impact of the Extracellular Matrix on Immunotherapy Success 17.1 Introduction 17.2 Extracellular Matrix Remodeling and Immune Tumor Microenvironment 17.2.1 ECM Components 17.2.2 Immunomodulatory Roles of ECM: Matrix Components as Promoters of Immune Response 17.3 Immune Response in Tumors 17.3.1 The Cancer-Immunity Cycle 17.3.2 Immune-Cell Trafficking in the Stroma 17.3.3 The Role of the Matrisome in Tumor Inflammation and Cancer 17.4 Cancer Immunotherapy 17.4.1 Improving Immune-Mediated Antitumor Response 17.4.2 Immune Checkpoint Inhibitors 17.4.3 ECM Components as Emerging Players in Immunotherapy 17.5 Therapeutic Combinations to Enhance Immunotherapy Achievement 17.5.1 Influence of Radiotherapy on ECM and the Stroma 17.5.2 Chemotherapy Induces ECM Remodeling and Promotes the Immune Response 17.5.3 Combined Strategies: Where Are We and Where Are We Going 17.6 Concluding Comments References Chapter 18: Exploiting Hyaluronan-CD44 Network in Tumor Therapy 18.1 Introduction 18.1.1 Hyaluronan Synthesis and Catabolism 18.1.2 CD44 18.2 Roles of Hyaluronan-CD44 Network in Tumors 18.2.1 Growth/Survival 18.2.2 Epithelial-to-Mesenchymal Transition (EMT) and Differentiation 18.2.3 Invasion/Metastasis 18.2.4 Drug Resistance 18.2.5 Tumor Stem Cell Properties 18.3 Hyaluronan/CD44 Network Targeting 18.3.1 Nanomedicine 18.3.2 Antibodies 18.3.3 Peptides 18.3.4 Chemically Modified Hyaluronan 18.3.5 Gene Therapies 18.4 Conclusions References Chapter 1: Small leucine-rich proteoglycans regulate cancer cell growth, apoptosis-and associated inflammation -- Chapter 2: The role of decorin in cancer -- Chapter 3: The mystery of syndecan-1 in tumor development and progression -- Chapter 4:Syndecan-2 Biology and its Role in Colorectal Carcinoma -- Chapter 5: Versican in Tumor Progression, Tumor-Host Interactions and Cancer Immunotherapy -- Chapter 6:Circulating proteoglycans/glycosaminoglycans as cancer biomarkers -- Chapter 7: Hyaluronan in the Extracellular Matrix of hematological and solid tumors. Its biological effects" -- Chapter 8: Heparanase: a paramount enzyme for cancer initiation, progression and metastasis -- Chapter 9: Laminins and matrix metalloproteinases connection: a subtle relationship that can go wrong in a tumor context, particularly if CD44 gets involved -- Chapter 10:Basement membrane, collagen, and fibronectin: physical interactions with cancer cells -- Chapter 11: Integrins in cancer: re-focusing on the tumor microenvironment -- Chapter 12: Adipose compounds in breast tumor extracellular matrix -- Chapter 13: Extracellular matrix as a metabolic niche in cancer -- Chapter 14: The role of inflammatory cells in tumor angiogenesis -- Chapter 15: Cancer angiogenesis and its master regulator perlecan -- Chapter 16: The microRNA-extracellular matrix interplay in breast cancer -- Chapter 17: The impact of the extracellular matrix on immunotherapy success -- Chapter 18: Exploiting hyaluronan-CD44 network in tumor therapy