Stem Cells. From Biology to Therapy

Stem Cells
Contents
Preface
Part I Basic Biology
     1 Epigenetic Regulation in Pluripotent Stem Cells
          1 Introduction
          2 DNA Methylation
          3 Histone Modifications and Histone Variants
          4 Higher-Order Structure of Chromatin
          5 X-Chromosome Inactivation
          6 Regulation of ESC Pluripotency and Differentiation by miRNAs
          7 Telomere Function and Genomic Stability in ESCs
          8 Imprinting and ESC Stability
          9 Epigenetic Interconversion among Mouse ESCs, EpiSCs, and Human ESCs
          10 Summary
          References
     2 Induced Pluripotent Stem Cells
          1 Introduction
               1.1 What Is Nuclear Reprogramming?
               1.2 Knowledge Obtained Using ES Cells
               1.3 The Blind Side of ES Cells
          2 iPSCs
               2.1 Discovery of the Reprogramming Factors
               2.2 The Sources of iPS Cells
               2.3 The Generation of iPSCs
          3 Application of iPS Cells
               3.1 iPS Cells as Disease Models
               3.2 iPSCs for Regenerative Medicine
          4 Conclusions
          Acknowledgments
          References
     3 Naturally Occurring Adult Pluripotent Stem Cells
          1 Introduction
          2 What Are Adult Pluripotent Stem Cells?
          3 What Are Progenitor Cells?
          4 Isolation and Characterization of Pluripotent Stem Cells
          5 Differences Between Induced Pluripotent Stem (iPS) Cells and Naturally Occurring Adult Pluripotent Stem Cells 69
          6 Locations of Adult Pluripotent Stem Cells
          7 Normal Functions of Adult Pluripotent Stem Cells
          8 Obtaining Adult Pluripotent Stem Cells
          9 The Use of Adult Pluripotent Stem Cells in Regenerative Medicine
          10 Proposed Uses for Adult Pluripotent Stem Cells
          Acknowledgments
          References
     4 Spermatogonial stem cell (SSCs) system
          Abbreviations
          1 Introduction
          2 Understanding Stem Cell Genes
               2.1 Techniques for Identifying the Anatomy of the Stem Cell
          3 The Mammalian Spermatogonial Stem Cell
          4 Crucial Signaling Pathways in Regulating the Fate of SS Cells
               4.1 Src Signaling Pathway
               4.2 Phosphoinositide 3-Kinase (PI3K)/Akt Pathway
               4.3 Ras/Erk1/2 Signaling Pathway
               4.4 Smad Signaling Pathway
          5 MicroRNAs in the Regulation of Spermatogenesis
          6 Isolation, Characterization, and Culture of Mouse and Human Spermatogonia 106
               6.1 Isolation and Characterization of Rodent Spermatogonia
                    6.1.1 C-kit in Immature Testis
                    6.1.2 C-kit and GFRα-1 in Adult Testis
                    6.1.3 Other Studies and Markers for Mouse SS Cells
                    6.1.4 Isolation and Characterization of Adult Mouse SS Cells and Aging
               6.2 Isolation and Characterization of Human Spermatogonia
                    6.2.1 GPR125
                    6.2.2 Other Human Spermatogonial Markers
          7 The Significance of SS Cells Outside Their Niche: The Emergence of the Pluripotent Adult Stem Cell
          8 Concluding Remarks: Summary of the Significance of SS Cells
          Acknowledgments
          References
     5 Stem Cell Dormancy: Maintaining a Reserved Population
          1 Introduction
          2 Purpose of Stem Cell Quiescence and Dormancy
          3 History
          4 Factors Regulating Quiescence
               4.1 Extrinsic Factors Regulating Quiescence: The Stem Cell Niche
               4.2 Intrinsic Regulators of Quiescence
          5 Factors Regulating Dormancy
               5.1 Extrinsic Factors Regulating Dormancy: The Stem Cell Niche
               5.2 Intrinsic Regulators of Dormancy
          6 Cancer Relevance
          References
     6 Stem Cells in the Adult Brain: Neurogenesis
          1 Brief Historical Significance
          2 Identity and Properties of Adult Neural Stem Cells
          3 Adult Neurogenesis Niche
               3.1 The Subventricular Zone (SVZ)
               3.2 The Subgranular Zone (SGZ)
          4 Regulation of Adult Neural Stem Cells and Neural Progenitor Cells
               4.1 Extrinsic Signals
               4.2 Intrinsic Regulators
               4.3 Neuronal Activity Control
          5 Evolving Concepts of Adult Neural Stem Cells
               5.1 The Lineages of Adult Neural Stem Cells
               5.2 Adult Neural Stem Cell Heterogeneity
               5.3 Adult Neurogenesis in Humans
          6 Conclusions
          Acknowledgments
          References
     7 Embryonic Stem Cells
          1 Embryonic Development
          2 Derivation of ES Cells
          3 Basic Properties of ES Cells
          4 Similarities and Differences Among ES Cells Derived from Different Species
          5 Culturing ES Cells
          6 Differentiation of ES Cells and Other Pluripotent Cells
          7 Other Stem Cell Populations, ES-Like Cells, Primordial Germ Cell, and Epiblast Cells
          8 iPSCs
          9 Uses of ES Cells and Other Pluripotent Cells
          References
          Further Reading
Part II Laboratory Methods
     8 Cardiomyocytes from Human Embryonic Stem
          1 Introduction
          2 Signaling and Regulation in Heart Development: Molecular Insights into hESC Differentiation
               2.1 Essential Signaling Pathways in Cardiac Development
               2.2 Transcription Factors within Cardiac Regulatory Networks
          3 Differentiation of hESCs to Cardiomyocytes
               3.1 Spontaneous Differentiation by Embryoid Body Formation
               3.2 END2 Coculture
               3.3 Directed Differentiation in Defined Media
          4 Characterization of hESC-Derived Cardiomyocytes
               4.1 Molecular Phenotype
               4.2 Transcriptome Analysis
               4.3 Electrophysiological Characterization
          5 Scale-Up and Enrichment of hESC-CMs
               5.1 Scale-Up Platforms
               5.2 hESC-CM Enrichment Strategies
          6 Translational Research in hESC-CMs
               6.1 Cell Therapy for Heart Regeneration
               6.2 hESC-CMs for Drug Discovery
          7 Conclusions and Future Outlook
          Acknowledgements
          References
     9 Cloned Mice from Adult Stem Cells
          1 Introduction
          2 The Success Rate of Mammalian Cloning and Differentiation Status of Donor Cells
               2.1 Speculation That the Cloning Efficiency from Adult Stem Cells Is Better Than from Differentiated Cells
               2.2 Cloned Mice from Hematopoietic Stem Cells
               2.3 Cloned Mice from Neural Stem Cells
               2.4 Cloned Mice from Mesenchymal Stem Cells
               2.5 Cloned Mice from Keratinocyte Stem Cells
               2.6 Cloned Deer from Antler Stem Sells
               2.7 Current Understanding of Adult Stem Cells as Nuclear Donors
          3 Epigenetic Status of Cloned Animals
               3.1 Aberrant Epigenetic Modifications in Cloned Embryos
               3.2 Effects of Histone Deacetylase Inhibitors
               3.3 Somatic Cell Nuclear Transfer and Telomere Length
          4 Application of Somatic Cell Nuclear Transfer Technology
               4.1 Establishment of ES Cells Derived from SCNT-Generated Blastocysts
               4.2 Therapeutic Application of ntES Cells
               4.3 Generating Cloned Mice from ‘‘Unclonable’’ Strains
               4.4 Producing Offspring from Infertile Mice
               4.5 Possibility of Resurrecting Extinct Animals
          5 Conclusions
          References
     10 Cloned Mice from Embryonic Stem Cells
          1 Introduction
          2 Improvements in the Success Rate of Mouse Somatic Cell Cloning
          3 Establishment of ES Cells from Somatic Cells via Nuclear Transfer
               3.1 How Normal Are ntES Cells?
               3.2 Ethical Problems Regarding ntES Cells
               3.3 Avoiding Ethical Problems Associated with ntES Cells by Using Lethally Vulnerable Embryos, or Using Embryos without their Destruction
          4 The Value of Mouse Cloning Using an ntES Cell Line
               4.1 Applications of ntES Cell Techniques for Therapeutic Medicine
               4.2 Improving the Differentiation Potential of Parthenogenetic ES Cells by Nuclear Transfer
               4.3 Producing Offspring from Individual Mice, Including Infertile Mice
               4.4 The Possibility of Resurrecting an Extinct Animal
          5 Conclusions
          References
     11 Haploid Embryonic Stem Cells
          1 Introduction
          2 History and Rationale
               2.1 Haploidy in Evolution
               2.2 Haploid Somatic Cell Culture
               2.3 Attempts Towards Haploid ES Cell Culture
               2.4 Rationale
          3 Approaches to Haploid ES Cell Culture
               3.1 Production of Haploid Embryos
               3.2 Cell Culture Derivation
               3.3 Culture Conditions
               3.4 Generation of Stable Haploid ES Cell Lines
               3.5 Characterization of Haploid ES Cells
               3.6 Stable Growth and Genetic Stability
          4 Applications of Haploid ES Cells
               4.1 Semicloning
               4.2 Haploid Genetic Screens
          5 Concluding Remarks
          Acknowledgments
          References
          Notes added to proof
     12 Muscle Stem Cells: Their Discovery, Properties, and In-Vitro Manipulation
          1 Seeking the Source of Skeletal Muscle’s Vast Ability to Repair
               1.1 A Brief Overview of Skeletal Muscle Structure, Function, and Regeneration
               1.2 The Discovery of Satellite Cells Provides a Candidate Cellular Agent Driving Muscle Regeneration
               1.3 Improved Methods for Handling and Characterizing Satellite Cells Enrich Understanding, but Call into Question Muscle Stem Cell Status
          2 Vindicating the Satellite Cell as a Muscle Stem Cell: Verification as the Physiological Muscle Stem Cell
               2.1 Muscle Stem Cells Must Possess Two Key Traits
               2.2 Evidence Emerges for Satellite Cell Self-Renewal In Vivo, Reconfirming Them as the Physiological Muscle Stem Cell
               2.3 Satellite Cells Represent a Heterogeneous Population with Varying Potentials
               2.4 Cellular Polarization and Stochastic Events Facilitate Satellite Cell Self-Renewal
               2.5 Other Cell Types Can Contribute to Myogenesis, Albeit with Varying Efficacies
          3 Regulating Muscle Stem Cell Self-Renewal in Culture: In Vivo Lessons and In Vitro Implementations
               3.1 Muscle Stem Cell Fate Is Controlled by Multiple Layers of Regulation
               3.2 Niche Cues Orient Satellite Cell Polarity and Asymmetry
               3.3 Local Factors Crosstalk to Decide Satellite Cell Fate
               3.4 Systemic Factors Exert a Long-Range Influence on Satellite Cell Fate
               3.5 Mimicking the Muscle Microenvironment In Vitro
                    3.5.1 Soluble Factors
                    3.5.2 Substrate and Physical Factors
          4 Ongoing Optimization of Muscle Stem Cell Self-Renewal in Culture
          Acknowledgments
          References
     13 Nuclear Transfer for Cloning Animals
          1 Introduction and Brief Historical Overview
          2 Key Elements and Critical Aspects of NT Technology
               2.1 Nuclear Reprogramming and Epigenetics
                    2.1.1 DNA Methylation
                    2.1.2 Histone Modifications
                    2.1.3 Nuclear Reprogramming by the Blastocyst Stage in Cloned Embryos
                    2.1.4 Imprinting and Imprinted Genes in Cloned Animals
               2.2 Epigenetic Differences between Donor Ce
                    2.2.1 Embryonic Cell Cloning
                    2.2.2 Germ Cell Cloning
                    2.2.3 Somatic Cell Cloning
               2.3 Genetic Differences between Donor Cells
                    2.3.1 Genetic Integrity
                    2.3.2 Telomeres
                    2.3.3 Mitochondrial Heteroplasmy
                    2.3.4 Genetic Background
               2.4 Choice of Nuclear Donor Cell Cycle Stage
                    2.4.1 The Donor Cell Cycle
                    2.4.2 Cell Cycle Coordination to Maintain Normal Ploidy
                    2.4.3 Cell Cycle Coordination to Promote Reprogramming
               2.5 Reprogramming Ability of the Recipient Cell
               2.6 Enucleation
               2.7 NT Method
                    2.7.1 Nuclear Injection
                    2.7.2 Fusion
               2.8 Artificial Activation
               2.9 In Vitro Culture of Cloned Embryos
               2.10 Transfer of Cloned Embryos
               2.11 Pregnancy Monitoring and Progeny Pr
               2.12 Adult Clone Phenotypes
               2.13 Trans-Generational Effects
          3 Applications of NT in Different Species
               3.1 Non-Mammalian Species: Frog and Fish
               3.2 Laboratory Animal Species: Mouse, Rat, and Rabbit
               3.3 Farm Animal Species: Sheep, Cattle, Goat, Pig, Buffalo, and Horse
                    3.3.1 Safety of Food Products from Cloned Farm Animals
               3.4 Endangered Species and Companion Animals
               3.5 Humans and Nonhuman Primates
               3.6 Ethical and Animal Welfare Aspects of NT Research
               4 Future Perspectives of NT
               Acknowledgments
               References
     14 Induction of Pluripotent Stem Cells from Umbilical Cord Blood
          1 Introduction
          2 The iPSC Technology
          3 Sources of Human Cells for hiPSC Generation
          4 Cord Blood as the Premium Tissue for Reprogramming
          5 Reprogramming Human Cord Blood with Integrating Vectors
          6 Reprogramming Cord Blood with Non-Integrating Episomal System
          7 Epigenetic Memory and Genetic Stability of Blood-Derived iPSCs
          8 Concluding Remarks
          Acknowledgments
          References
     15 Development and Renewal of Ventricular Heart Muscle from Intrinsic Progenitor Cells
          1 Introduction
          2 Perspectives on Stem/Progenitor Cells in the Developing Heart
          3 Emergence of Cardiac Progenitors in the Embryo
          4 Specification of the Early Cardiogenic Fate
          5 Progenitors in the First Heart Field
          6 Progenitors in the Second Heart Field
          7 Regional Specification of the Developing Heart
          8 Epicardial Progenitor Cells
          9 Postnatal Cardiomyocyte Turnover
          10 Postnatal and Adult Cardiac Stem/Progenitor Cells
          11 Cardiac Stem/Progenitor Cells for Postnatal Myocardial Regeneration
          12 Conclusion
          References
Part III Stem Cell Therapy
     16 Gene Therapy of Genetic Diseases of Blood Cells
          1 Genetic Diseases of Blood Cells
          2 Allogeneic HSCT as Treatment of Genetic Diseases of Blood Cells
          3 Gene Therapy
          4 Severe Combined Immune Deficiency (SCID)
               4.1 Introduction
               4.2 SCID due to ADA Deficiency
               4.3 X-Linked SCID
          5 Wiskott–Aldrich Syndrome
          6 Chronic Granulomatous Disease
          7 Hemoglobinopathies
          8 Lysosomal Storage Diseases and Metabolic Diseases
          9 Gene Correction by Homologous Recombination
          10 Summary
          References
     17 Mesenchymal Stem Cells Characteristics, Niches, and Applications for Cell Therapy
          1 Introduction
          2 MSC Sources and Isolation
               2.1 Historical Perspective of MSCs
               2.2 Sources and Isolation of MSCs
               2.3 Bone Marrow Stem Cell Niche
          3 MSC Characteristics
               3.1 In Vitro Culture
               3.2 Differentiation
          4 MSCs and Immunomodulation
               4.1 MSC Effects on Immune Cells
               4.2 Mechanisms of MSC Immunosuppression
          5 MSC Therapy
               5.1 Animal Models
               5.2 Clinical Trials
          6 MSCs and Cancer
               6.1 MSCs: Cancer-Promoting or Cancer-Suppressive?
               6.2 MSCs as Delivery Vectors for Cancer Therapy
          7 Concluding Remarks
          Acknowledgments
          References
     18 Stem Cells and Parkinson’s Disease
          1 Introduction
               1.1 Parkinson’s Disease and the Nigrostriatal Dopaminergic System
               1.2 Current Therapy of PD
          2 Neuroregeneration and Cell Therapy
               2.1 Principle
               2.2 The Foundation of Neural Cell Transplantation in PD
          3 Novel Stem Cell Sources for Neural Cell Therapy
               3.1 Overview and Definitions
               3.2 Somatic Stem Cells
                    3.2.1 Fetal Neural Stem Cells
                    3.2.2 Adult Neural Stem Cells
                    3.2.3 Other Somatic Cell Types (e.g., Mesenchymal Stem Cells)
               3.3 Pluripotent Stem Cells
                    3.3.1 Overview
                    3.3.2 Pluripotent Stem Cells: Embryonic Stem Cells
                    3.3.3 Pluripotent Stem Cells: Induced Pluripotent Stem Cells
                    3.3.4 Markers of Pluripotency
          4 Neural and Dopaminergic Differentiation of Human Pluripotent Stem Cells
               4.1 Neural Induction and Early Midbrain Domain Patterning
                    4.1.1 Markers of Neural Differentiation
               4.2 Dopaminergic Differentiation
                    4.2.1 Markers of Dopaminergic Differentiation
          5 Neural Cell Sorting
          6 Current Challenges and Outlook
               6.1 Clinical Demands
               6.2 In-Vitro Assays
               6.3 Direct Conversion
               6.4 In-Vivo Recruitment
          7 Summary and Conclusion
          References
     19 Stem Cell-Based Approaches to Spinal Cord Injury
          1 Introduction
               1.1 Epidemiology
               1.2 Pathophysiology
               1.3 Stem Cell Transplantation Benefits
          2 Stem Cells: An Overview
          3 Endogenous Neural Progenitor Cells
               3.1 Bone Marrow Stem Cells, Mesenchymal Stem Cells, and Umbilical Cord Stem Cells
               3.2 iPS Cells
          4 Embryonic Stem Cells
          5 Stem Cell Growth
          6 Predifferentiation of ESC Cells
               6.1 OPCs
               6.2 MNP Cells
          7 Clinical Trials
          8 Clinical Concerns
          9 Summary and Conclusion
          References
     20 Therapeutics against Cancer Stem Cells: Targeting the Root of Cancer
          1 Introduction
          2 Cancer Stem Cells
               2.1 Properties of Cancer Stem Cells
               2.2 Complexities of the Cancer Stem Cell Model
          3 Stem Cell-Related Signaling Pathways
               3.1 Wnt/β-Catenin
               3.2 Hedgehog
               3.3 Notch
          4 Additional Cancer Stem Cell Targets
               4.1 NF-κB
               4.2 PI3K/AKT/mTOR
               4.3 Telomerase
          5 Cancer Stem Cell Niche
          6 CSCs in Drug Discovery
          7 Concluding Remarks
          References
     21 Translating Stem Cells to the Clinic: From Modeling Disease to CellularProducts
          1 Introduction
               1.1 Generation, Regeneration, and Cellular Plasticity: An Historical Overview
               1.2 The Birth of Stem Cell Research
          2 The Promises of Pluripotency
               2.1 Achieving Pluripotency in a Culture Dish: State of the Art
                    2.1.1 Embryonal Carcinoma Cells
                    2.1.2 Embryonic Stem Cells
                    2.1.3 Embryonic Germ Cells
                    2.1.4 Induced Pluripotent Stem Cells
               2.2 The Dark Side of Pluripotent Stem Cells: Slowing Down Therapeutic Applications
                    2.2.1 Ethical Issues
                    2.2.2 The Pluripotency-Associated Cancer Risks
                    2.2.3 Pluripotent-Associated Immunogenicity
               2.3 Pluripotent Cells and Differentiation: Raising Hopes for the Clinic
                    2.3.1 Generation of Clinically Relevant Cells in a Culture Dish
          3 Lineage Conversion and Plasticity: New Kids for the Future of Regenerative Medicine
          4 Multipotent Adult Stem Cells: The Alternative to Pluripotency
               4.1 Generalities
               4.2 Mesenchymal Stem Cells: On the Way to the Clinic
          5 Gene Editing and Disease Modeling
          6 Conclusions
          References
Part IV Stem Cells and Disease
     22 Cancer Stem Cells
          1 Introduction
          2 Identification and Characterization of the CSCs
               2.1 Identification
               2.2 Cell of Origin of CSCs
               2.3 Are CSCs a Rare Population within a Tumor?
               2.4 Quiescence of the Stem Cells
               2.5 Cell Plasticity
               2.6 Circulating Tumor Cells
          3 Signaling Pathways and Factors Involved in the Regulation of CSCs
               3.1 Wnt/β-Catenin Canonical Signaling Pathways
               3.2 Hedgehog (Hh) Signaling Pathway
               3.3 Notch Signaling Pathw
               3.4 PI3K/Akt/PTEN Signaling Pathway
               3.5 Tumor Suppressor p53
               3.6 MicroRNAs (miRNAs)
          4 CSCs and the Microenvironment
          5 Radiation and Chemotherapy Resistance of CSCs
          6 Targeting CSCs
               6.1 Targeting CSCs and Their Microenvironment
               6.2 Targeting CSCs while Sparing the Normal Stem Cells
          7 Conclusions
          References
     23 Normal and Neoplastic Stem Cells
          1 Introduction
          2 Characteristics and Functions of Stem cells
               2.1 General Characteristics
               2.2 The Hierarchy of the Hematopoietic System as Model
               2.3 Intestinal Stem Cells
               2.4 Regulatory Network
                    2.4.1 Wnt-Signaling
                    2.4.2 Notch Signaling
                    2.4.3 The Hedgehog–BMP Axis
                    2.4.4 The Polycomb Group Gene Bmi1
          3 Neoplastic Stem Cells
               3.1 Tumor as an Abnormal Organ
               3.2 Recent Evidence for Neoplastic Stem Cells in Acute Myeloid Leukemia and Breast Cancer
               3.3 Self-Renewal
               3.4 Deregulation of Signaling
               3.5 Epithelial–Mesenchymal Transition, Metastases, and Neoplastic Stem Cells
               3.6 Drug Resistance
          4 Implications of Neoplastic Stem Cells for the Treatment of Cancer
               4.1 Agents Targeting Surface Markers and Receptors
               4.2 Agents Targeting Neoplastic Stem Cell-Specific Signaling Pathways
               4.3 Targeting Downstream/Interacting Pathways of Neoplastic Stem Cell Signaling
               4.4 Epigenetic Approaches
               4.5 Combination Therapy Options
          5 Conclusions
          References
     24 Prostate Tissue Stem Cells and Prostate Cancer Progression
          1 Introduction
               1.1 Conceptual Overview: Stem Cells and Cancer Stem Cells
               1.2 Prostate Histology, Cell Lineages, and Morphogenesis
               1.3 Prostate Cancer Pathology
          2 Mouse Prostate Stem and Progenitor Cells
               2.1 Normal Prostate Tissue Reconstituting Cells
               2.2 Tumor Initiation and CSCs in Basal and Luminal Cell Compartments
          3 Human Prostate Stem Cells
               3.1 Normal Human Prostate (NHP) Cells and Immortalization
               3.2 CSC Analysis in Prostate Cancer Cell Lines and Xenografts
               3.3 Primary Human Prostate Cancer
          4 Molecular Mechanisms Regulating Prostate Cell Fate
          5 Outstanding Questions
          Acknowledgments
          References
     25 The Stem Cell Niche and Its Role in Self-Renewal, Aging, and Malignancy
          1 The Stem Cell Niche and Its Role in Stem Cell Self-Renewal
               1.1 Concept of the Stem Cell
                    1.1.1 Stem Cell Self-Renewal
                    1.1.2 Cell-Intrinsic Machinery Controls Stem Cell Self-Renewal
               1.2 Concept of the Stem Cell Niche and Regulation of Stem Cell Self-Renewal
                    1.2.1 Stationary Components of the Stem Cell Niche
                    1.2.2 Support Cells
                    1.2.3 Extracellular Components
          2 The Stem Cell Niche and Its Role in Aging
               2.1 Age-Associated Changes in Stem Cell Behaviors
                    2.1.1 Aging in Hematopoietic Stem Cells
                    2.1.2 Aging in Neural Stem Cells
                    2.1.3 Aging in Muscle Stem Cells
               2.2 Aging-Related Alterations in Cell-Intrinsic Signaling Pathways
               2.3 The Aging Stem Cell Niche
          3 The Stem Cell Niche and Its Role in Carcinogenesis
               3.1 Cancer Stem Cell Concept
                    3.1.1 Cancer Initiator Cells, the Origin of Cancer
                    3.1.2 Cancer Stem Cells, Cancer Progression, Metastasis, and Relapse
                    3.1.3 Cancer Stem Cells are Relatively Chemo- and Radio-Resistant
                    3.1.4 Complexity of Cancer Stem Cells
               3.2 Cancer Stem Cell Niches
                    3.2.1 Contribution of the Niche Microenvironment to Tumorigenesis
                    3.2.2 The Role of the Normal Stem Cell Niche in Tumorigenesis
                    3.2.3 The Potential Components of CSC Niches
                    3.2.4 The Contribution of BM-Derived Inflammatory Cells to the CSC Niche
                    3.2.5 The CSC Niche and Drug Resistance
          References
     26 Stem Cells and Colon Cancer
          1 Colorectal Cancer
               1.1 Stochastic versus Hierarchical Model in Cancer Origin
               1.2 Colon Crypt and Cancer Stem Cell Characterization
               1.3 Stemness Niche: Definition, Role, and Pathways Involved in Its Modulation
          2 Treatment Option Overview: Strategy of Treatment by Stage
               2.1 Adjuvant Chemotherapy for Stage II CRC
               2.2 Adjuvant Chemotherapy for Stage III CRC
               2.3 Adjuvant Chemotherapy for Stage IV and Recurrent Colon Can
               2.4 Target Therapy: Bevacizumab, Cetuximab/Panitumumab
               2.5 Alternative Therapies: mTOR, Protein Kinase C, and Src Inhibitors
          3 Targeting the Differentiation and Survival Signaling in CSCs
               3.1 Immunotherapy
          Acknowledgments
          References
Index