Cancer Stem Cell Resistance to Targeted Therapy (Resistance to Targeted Anti-Cancer Therapeutics, 19)

This book represents an up-dated summary of the state of the art of the characterization of cancer stem cell/ cancer initiating cell (CSC/CIC) properties. An overview of the definition and biological properties of CSCs/CICs as well as the role of these cells in determining the resistance to standard and immune-based therapies is provided. It also discusses limitations in the achievement of a definitive biological characterization of CSCs/CICs due to their high extent of plasticity and heterogeneity that is also mutually driven by the interaction of these cells with the tumor microenvironment. The limitations in targeting CSCs/CICs with immunotherapy are also explained together with explorative combination approaches that could increase the susceptibility of these cells to the recognition by immune cells. This book is conceived for a broad audience, including students, teachers, scientific experts. The critical revision of available results in terms of immunological profile of CSCs/CICs and the efficacy in targeting these cells by immunological approaches, results in a comprehensive and up to date recapitulation of the field and provides interesting suggestions on how to focus future investigations in order to assess the role of CSCs/CICs as prognostic and predictive biomarkers of responsiveness to therapies for cancer patients. Aims and Scopes 5 About the Editors 6 Preface 10 Contents 13 Contributors 15 Series Editor Biography 17 Cancer Stem Cells: From Birth to Death 18 1 Origin and Identity of Cancer Stem Cells 20 1.1 Models of Tumor Growth 20 1.2 Cancer Stem Cell Isolation 22 1.3 Xenotransplantation Versus Genetic Tracing and Lineage Ablation Approaches 23 1.4 The Hallmarks of Cancer Stem Cells 24 2 Transcriptional Networks and Pluripotent Genes 26 2.1 The WNT Signaling 27 2.2 The Hedgehog Pathway 28 2.3 The Notch Pathway 29 2.4 The Hippo Pathway 29 2.5 The TGF-β Pathway 30 3 Developing Novel Tools to Target the Therapy-Resistant CSC Population 31 3.1 What Makes CSCs Resistant to Conventional Treatments? 32 3.2 Stemness Modulator Drugs 33 3.3 Targeting the “Metabostemness” 34 3.4 Targeting Tumor Microenvironment 35 4 Concluding Remarks 36 References 37 A Cancer Stem Cell Perspective on Minimal Residual Disease in Solid Malignancies 48 1 Introduction 49 2 The Developing Cancer Stem Cell Model 50 3 Cancer Stem Cells and Minimal Residual Disease 53 4 Cancer Stem Cells: The Microenvironment and Dedifferentiation 55 5 Cancer Stem Cells and Clinical Trials 58 6 Outlook 60 References 61 Cancer Stem Cells in Lung Cancer: Roots of Drug Resistance and Targets for Novel Therapeutic Strategies 67 1 Lung Cancer Stem Cells (CSCs): Introduction 69 1.1 Stem Cells in Lung Cancer 70 1.2 Lung CSC Markers 71 2 Lung CSCs and Drug Resistance 75 2.1 Clinical Relevance of CSCs for Lung Cancer Treatment 75 2.1.1 Lung Cancer Treatments, Drug Resistance, and CSCs 75 2.1.2 Prognostic Significance of Lung CSC Markers 77 2.2 Molecular Pathways Sustaining Intrinsic Drug Resistance of Lung CSC 79 2.2.1 DNA Damage Response and Anti-apoptotic Pathways 79 2.2.2 Proteins Involved in Drug Efflux and Detoxification 80 2.2.3 Self-Renewal Pathways 81 2.2.4 Intrinsic Quiescence 84 2.3 Tumor Microenvironment Signaling Promoting CSC Drug Resistance 85 2.3.1 Epithelial to Mesenchymal Transition and Drug Resistance 87 2.3.2 Epithelial to Mesenchymal Transition and Acquisition of CSC Properties 88 3 Novel Therapeutic Strategies Targeting Lung CSCs 90 3.1 Targeting Intrinsic CSC Drug Resistance 90 3.2 Targeting Tumor Microenvironment Cross Talk 92 4 Conclusions and Future Perspectives 94 References 96 Overexpression of YY1 Regulates the Resistance of Cancer Stem Cells: Targeting YY1 109 1 Introduction 110 1.1 Properties of Cancer Stem Cells 110 1.2 Regulation of Cancer Stem Cells 111 2 Resistance of Cancer Stem Cells: Role of Cancer Stem Cell Transcription Factors in Resistance 111 3 Targeting Cancer Stem Cells 114 4 YY1 and Its Association with the Transcription Factors of Cancer Stem Cells 117 5 YY1 Inhibitors and Reversal of Resistance [88] 119 6 Concluding Remarks 122 References 123 Cancer Stem Cell Challenges in Melanoma Characterization and Treatment 130 1 Introduction 132 2 Cancer Stem Cells and Melanoma: Definition and Identification 133 3 Melanoma Cancer Stem Cells: Open Questions 135 4 Melanoma Heterogeneity and Plasticity: Cause or Result of Therapy Resistance? 136 5 Targeting Melanoma Cancer Stem Cells 138 6 Conclusions 141 References 141 Harnessing the Immune System to Target Cancer Cells 151 1 Introduction 152 2 Cancer Vaccines 153 2.1 Tumor-Associated Antigens (TAAs) 153 2.2 DNA/RNA and Virus-Based Vaccines 155 2.3 Dendritic Cells and Whole-Cell Vaccines 156 3 Immune Checkpoint Blockade 156 4 Adoptive Cell Therapy 157 5 Conclusions 159 Bibliography 159 Targeting Leukemia Stem Cells and the Immunological Bone Marrow Microenvironment 166 1 Introduction 167 2 The BM Immune Microenvironment 169 3 Immunophenotypic and Functional Features of LSCs 171 4 Targeting LSC-Associated Antigens to Overcome Therapeutic Resistance 173 5 Conclusions 179 References 179 Crosstalk Between Prostate Cancer Stem Cells and Immune Cells: Implications for Tumor Progression and Resistance to Immunotherapy 186 1 Introduction 188 2 CSCs: An Operational Definition 190 3 Role of CSCs in the Evolution of Prostate Cancer 191 4 Role of CSCs in the Development of Prostate Cancer Metastases 194 5 Interactions Between PCSCs and the Immune System 198 5.1 The Immune Infiltrate in Prostate Cancer 199 5.2 Prostate Cancer Generates an Immunosuppressive Microenvironment 201 5.3 PCSC-Mediated Mechanisms of Immunosuppression in Prostate Cancer 203 6 Immunotherapy Applied to PCSCs 205 6.1 How to Target PCSCs with Immunotherapy 207 7 Conclusion and Future Directions 210 7.1 Identification of PCSC-Specific Cell Surface Markers 211 7.2 Strategies to Favor Tumor Infiltration by Activated T Cells 211 7.3 Strategies to Overcome Immune Suppression 213 References 215 Cancer Stem Cells: The Players of Immune Evasion from Immunotherapy 235 1 Introduction 236 2 Major Histocompatibility Complex (MHC), Tumor-Associated Antigen Expression in CSCs/CICs, and Cell-Mediated Immune Responses 240 3 Antibody-Mediated Targeting of CSCs/CICs 242 4 CSCs/CICs Display Immunomodulating Properties 243 4.1 Soluble Factors, Cytokines, Chemokines, and Adhesion Molecules 243 4.2 Immune Checkpoint, Enzyme, and Signaling Molecules 245 5 Micro-RNAs (miRNAs) 245 6 CSCs/CICs in Tumor Dormancy and Immune Evasion 246 7 Targeting CSCs/CICs with Immunotherapy 247 8 Cancer Vaccines 248 9 Innate Immune Responses 248 10 Immune Checkpoint Blockade and TME Targeting 249 11 Adoptive Cell Therapy 250 12 Conclusions and Perspectives 251 References 252 Index 262 Front Matter ....Pages i-xix Cancer Stem Cells: From Birth to Death (Alice Turdo, Miriam Gaggianesi, Aurora Chinnici, Giorgio Stassi, Matilde Todaro)....Pages 1-30 A Cancer Stem Cell Perspective on Minimal Residual Disease in Solid Malignancies (Maartje van der Heijden, Louis Vermeulen)....Pages 31-49 Cancer Stem Cells in Lung Cancer: Roots of Drug Resistance and Targets for Novel Therapeutic Strategies (Cecilia Gardelli, Gabriella Sozzi, Luca Roz, Giulia Bertolini)....Pages 51-92 Overexpression of YY1 Regulates the Resistance of Cancer Stem Cells: Targeting YY1 (Benjamin Bonavida)....Pages 93-113 Cancer Stem Cell Challenges in Melanoma Characterization and Treatment (Alessandra Tuccitto, Chiara Castelli, Malcolm Ronald Alison, Michela Perego)....Pages 115-135 Harnessing the Immune System to Target Cancer Cells (Cristina Maccalli)....Pages 137-151 Targeting Leukemia Stem Cells and the Immunological Bone Marrow Microenvironment (Cristina Maccalli, Sarah K. Tasian, Sergio Rutella)....Pages 153-172 Crosstalk Between Prostate Cancer Stem Cells and Immune Cells: Implications for Tumor Progression and Resistance to Immunotherapy (Matteo Bellone, Sara Caputo)....Pages 173-221 Cancer Stem Cells: The Players of Immune Evasion from Immunotherapy (Saad Rasool, Sergio Rutella, Soldano Ferrone, Cristina Maccalli)....Pages 223-249 Back Matter ....Pages 251-256 This book represents an updated summary of the state of the art of the characterization of cancer stem cell/cancer initiating cell (CSC/CIC) properties. Experts provide an overview of the definition and biological properties of CSCs/CICs as well as the role of these cells in determining the resistance to standard and immune-based therapies. It also discusses limitations in the achievement of a definitive biological characterization of CSCs/CICs due to their high extent of plasticity and heterogeneity that is also mutually driven by the interaction of these cells with the tumor microenvironment. The limitations in targeting CSCs/CICs with immunotherapy are also explained together with explorative combination approaches that could increase the susceptibility of these cells to the recognition by immune cells. This book is conceived for a broad audience, including students, teachers, scientific experts. The critical revision of available results in terms of immunological profile of CSCs/CICs and the efficacy in targeting these cells by immunological approaches, results in a comprehensive and up to date recapitulation of the field and provides interesting suggestions on how to focus future investigations in order to assess the role of CSCs/CICs as prognostic and predictive biomarkers of responsiveness to therapies for cancer patients