The Systemic Effects of Advanced Cancer: A Textbook on Cancer-Associated Cachexia

Description

This textbook discusses the systemic consequences of cancer, covering a range of topics from tumor-promoting systemic effects to the development of cachexia, as summarized in the introductory chapter 1. Part I of this textbook focuses on tumor-promoting systemic effects and begins with a chapter on how tumor-derived extracellular vesicles and particles lay the foundation for future metastases (Chapter 2). Chapter 3 discusses how metastatic cells that have colonized the bone impact the local bone microenvironment, neighboring muscles, and host physiology. Chapter 4 summarizes the available strategies for targeting metastatic cancer and emphasizes the need to incorporate a systemic view of the disease. Following this overview of the systemic effects of cancer progression, Part II of the textbook discusses cancer-induced cachexia, a debilitating systemic effect of advanced cancer. Chapters 5-7 examine the key signaling pathways (interleukin-6/GP130, NF-kB, and muscle proteolysis) that drive the development of cancer cachexia. Chapters 8 and 9 in Part III of this textbook explore how toxicities from anti-cancer therapy are associated with the onset of cachexia in cancer patients, and provide insight into potential approaches to simultaneously target both cancer and cachexia. Chapters 10 and 11 (Part IV) conclude this textbook by outlining promising approaches for the diagnosis and treatment of cachexia as well as strategies to prevent the development of cachexia through exercise. An understanding of the systemic effects of cancer is essential for the design of effective anti-cancer and anti-cachexia treatment strategies. As such, this textbook provides key information for both students and scientists engaged in cancer research and oncology. Contents A Systemic View of Metastatic Disease: Inter-Organ Crosstalk and Therapeutic Implications 1 Author and Text Introductions References Part I: Systemic Regulation in Metastatic Disease Systemic Regulation of Metastatic Disease by Extracellular Vesicles and Particles Learning Objectives 1 Introduction 2 Architectural Remodeling of the Local Microenvironment 2.1 ECM Degradation 2.2 Fibroblast Reprograming 3 No Immune Cells Are Immune to EV Targeting 3.1 Progenitors 3.1.1 Recruiting HSPCs to Facilitate the Establishment of Pre-metastatic Niche 3.1.2 Inducing the Development of MDSCs and Associated Immunosuppression 3.2 Innate Immune System 3.2.1 Promoting Macrophage Polarization Toward an Anti-inflammation and Pro-tumor Phenotype 3.2.2 Impairing the Priming of Cytotoxic T Cells by Dendritic Cells 3.2.3 Escaping from Natural Killer Cell-Mediated Immunosurveillance 3.2.4 Inducing Neutrophil Polarization and NET Formation to Promote Tumor Growth and Metastasis 3.3 Adaptive Immune System 3.3.1 Suppressing the Proliferation and Activation of T-lymphocytes 3.3.2 Altering the Development of B-lymphocytes 4 Angiogenesis 5 Vascular Permeability 6 PMN Formation and Metastatic Organotropism 6.1 Local Metastasis to Lymph Nodes 6.2 Distant Organotropic Metastasis for Lung, Liver, Bone, and Brain 6.2.1 Lung Metastasis 6.2.2 Liver Metastasis 6.2.3 Bone Metastasis 6.2.4 Brain Metastasis 7 Concluding Remarks and Future Directions 7.1 Summary 7.2 Future Directions 7.2.1 Comprehensive Functional Characterization of the EVP Cargos 7.2.2 Tracking of Tumor-Derived EVPs In Vivo 7.2.3 Potential Role of Tumor-Derived EVPs in Other Systemic Complications of Cancer 7.2.4 EVPs as Biomarkers for Diagnosis 7.2.5 EVPs as Therapeutic Targets and Deliverables References Bone Metastases: Systemic Regulation and Impact on Host Learning Objectives 1 Introduction 2 Bone Metastases 2.1 Osteolytic Bone Metastases 2.2 Osteoblastic Bone Metastases 3 Cancer and Muscle Dysfunction 3.1 Bone-Derived Factors Impacting Muscle 3.2 Bone Metastases-Induced Muscle Dysfunction 4 Conclusion References Targeting Metastatic Disease: Challenges and New Opportunities Learning Objectives 1 Successful Examples for Targeting Metastasis 1.1 Bisphosphonates and Denosumab 1.2 Immunotherapy 2 Genomic Evolution of Primary Tumor and Metastatic Colonies 3 Targeting the Metastasis Cascade 3.1 Preventing Metastasis 3.2 Targeting Metastasis 4 Systemic Changes in Metastasis: Metabolic Changes 4.1 Bioenergetics 4.2 Biosynthesis in Metastasis 4.3 Redox Hemostasis in Metastasis 4.4 Systemic Metabolism Influences on Tumor Progression 5 Conclusions and Future Perspectives References Additional References Part II: Cachexia: A Debilitating Systemic Effect of Cancer Signaling Pathways That Promote Muscle Catabolism in Cachexia Learning Objectives 1 Introduction 2 Catabolic Pathways Mediating Cancer-Induced Cachexia 2.1 Systemic Inflammation 2.2 Transforming Growth Factor-beta Signaling 2.3 Glucocorticoids 2.4 Metabolic Alterations: Insulin Resistance and Hypermetabolism 2.5 Decreased Food Intake and Nutrient Availability 3 Molecular Mechanisms Contributing to Muscle Loss 3.1 Reduced Growth-Promoting Pathways 3.2 Enhanced Proteolysis Via the Proteasome and Autophagy 3.2.1 UPS Activation in Human Cancer Cachexia 3.3 Excessive Breakdown of Myofibrils in an Ordered Fashion 3.3.1 Degradation of Myofibrillar Proteins in a Specific Order 3.3.2 Loss of Desmin IF Precedes and Promotes Myofibril Destruction 3.3.3 Early Perturbations of Structural and Signaling Modules on the Muscle Membrane Promote Desmin Filament Disassembly 4 Conclusions and Future Perspectives References The Role of Interleukin-6/GP130 Cytokines in Cancer Cachexia Learning Objectives 1 Introduction 2 The GP130 Cytokine Family 3 Cytokines Documented in Cancer Cachexia 4 Conclusions and Future Perspectives References NF-kB Signaling in the Macroenvironment of Cancer Cachexia Learning Objectives 1 Introduction 1.1 NF-kappaB Regulation 1.2 Canonical and Non-canonical NF-kappaB Pathway 1.3 NF-kappaB Signaling in Healthy Skeletal Muscle 2 NF-kappaB Signaling in Pancreatic Cancer 2.1 Role of NF-kappaB in PDAC Initiation and Progression 2.2 NF-kappaB Regulates Angiogenesis and EMT to Promote Metastasis 2.3 NF-kappaB Increases Chemoresistance in PDAC 3 NF-kappaB Dependent Myofiber Atrophy and Muscle Dysfunction in Cancer Cachexia 3.1 NF-kappaB Activates the Ubiquitin Proteasome to Mediate Muscle Atrophy 3.2 NF-kappaB and the UPS in Cancer Cachexia 3.3 Beyond the Ubiquitin Proteasome System: Other Roles of NF-kappaB in Muscle Atrophy 4 NF-kappaB Role in Muscle Regeneration in Cancer Cachexia 4.1 Events in Muscle Regeneration and Satellite Stem Cells 4.2 NF-kappaB Prevents MPC Differentiation Leading to Muscle Wasting in Cachexia 4.3 Multiple Mechanisms of NF-kappaB Mediated Inhibition of MPC Differentiation 5 Conclusions and Future Perspective References Part III: Therapy-Induced Muscle Wasting Therapy-Induced Toxicities Associated with the Onset of Cachexia Learning Objectives 1 Introduction 2 Chemotherapy 3 Chemotherapy-Associated Cachexia: Phenotype and Mechanisms 4 The Impact of Cancer and Chemotherapy on Muscle Metabolism 5 Strategies to Counteract Chemotherapy Side Effects 5.1 Mitochondria and Exercise 5.2 Activin Signaling 5.3 Bone-Muscle Cross Talk 5.4 Nutrition 5.5 Amino Acids and Their Derivatives 5.6 Ghrelin 6 Conclusion and Perspectives References Bone-Muscle Crosstalk in Advanced Cancer and Chemotherapy Learning Objectives 1 Introduction 2 Tumor Metastasis to Bone 3 Skeletal Muscle Weakness in Advanced Cancer with Bone Metastases 4 Chemotherapy-Induced Bone Loss and Muscle Weakness 5 Preventing Bone Loss Improve Muscle Function 6 Conclusions and Future Perspectives References Part IV: Preventing and Targeting Cachexia in Cancer New Developments in Targeting Cancer Cachexia Learning Objectives 1 Targeting Patients with Cancer Cachexia 1.1 Diagnostic, Staging, Severity, and Phase Criteria 1.1.1 Diagnostic Definition 1.1.2 Phase of Cachexia 1.1.3 Complexities in Terminology 1.1.4 Screening Patients with Cachexia 1.1.5 Cross-sectional Imaging Nutritional Assessment CT MRI Contrast-Enhanced Ultrasound 1.2 Patient-Specific Factors 1.2.1 Sexual Dimorphism 1.2.2 Genetics 2 Identification of Novel Targets in Cachexia 2.1 Pathophysiological Mechanisms 2.1.1 Protein Metabolism 2.1.2 Autophagy 2.1.3 Neural Innervation of Skeletal Muscle 2.1.4 Fat-Muscle Crosstalk 2.2 Mediators of Cachexia 2.2.1 PTHrP 2.2.2 TWEAK 2.2.3 ZIP 14 2.2.4 Macrophage Inhibitory Cytokine1/Growth Differentiation Factor 15 2.2.5 Myostatin and Activin A 2.2.6 Angiotensin-II 2.2.7 Micro-RNAs 2.2.8 Interleukins 2.3 Mitochondria 2.3.1 Muscle Regeneration 3 Target Lessons Learnt from Recent Cachexia Trials 4 Future Developments 5 Conclusions and Future Perspectives References Exercise: A Critical Component of Cachexia Prevention and Therapy in Cancer Learning Objectives 1 Introduction 2 Defining Cancer Cachexia 3 Associations of Exercise, Physical Activity and Risk of Developing Cancer 4 Exercise and Physical Activity in Preventing and Treating Cancer Cachexia 4.1 Aerobic Exercise Training and Cancer Cachexia 4.2 Resistance Training and Cancer Cachexia 5 Conclusions and Perspectives References