Signal Transduction in Cancer Metastasis (Cancer Metastasis - Biology and Treatment, 15)

This book examines the signal mechanisms responsible for triggering a series of phenotypical changes of primary tumor which may lead to final colonization of the tumor in a second home. It highlights the initial stage of tumor metastasis. Preface Contents Contributors 1 Overview of Signal Transduction in Tumor Metastasis 1.1 Introduction 1.2 Signaling for the Initiation of Tumor Metastasis 1.3 Signaling for Intravasation 1.4 Signaling for Tumor Progression in Circulation 1.4.1 Anti-Anoikis of Circulating Tumor Cell 1.4.1.1 The Basic Concept for Anoikis 1.4.1.2 Signal Mechanism for Anti-Anoikis of Tumor Cell in Circulation 1.4.2 Signaling for Extravasation 1.5 Signaling for Homing and Survival of the Tumor in the Metastatic Loci 1.6 Conclusion and Perspective References 2 Microenvironment Triggers EMT, Migration and Invasion of Primary Tumor via Multiple Signal Pathways 2.1 Introduction 2.2 Phenotypical Changes of Tumor Cells in the Initial Stage of Tumor Metastasis: EMT, Migration and Invasion of Primary Tumor 2.2.1 Epithelial--Mesenchymal Transition: the Initiation Step of Tumor Metastasis 2.2.1.1 Tumor Migration: The Essential Driving Force for Metastasis 2.2.1.2 Tumor Invasion in Metastasis 2.2.2 Microenvironment in the Primary Tumor Locus 2.2.2.1 The Constitution of Tumor Microenvironment 2.2.2.2 The Effect of Inflammation on Tumor Progression 2.3 Signal Transduction Triggered by Metastatic Factors Within Microenvironment 2.3.1 HGF/c-Met 2.3.1.1 The HGF-cMet Signaling 2.3.1.2 The Role of HGF/SF-Met Signaling in Tumor Progression 2.3.1.3 Blockade of HGF/c-Met for Prevention of Tumor Metastasis 2.3.2 TGF-β 2.3.3 The Integrin-ECM Engagement 2.3.3.1 The Integrin-Mediated Signaling 2.3.3.2 Altered Integrin Signaling Promotes Tumor Progression 2.3.3.3 Crosstalk of Integrin Signaling With Other Pathway 2.3.3.4 Targeting Integrin Signaling for Prevention of Tumor Progression 2.4 Conclusion and Perspective References 3 The ERK1/2 MAP Kinase Signaling Pathway in Tumor Progression and Metastasis 3.1 Introduction 3.2 Hyperactivation of the Ras-ERK1/2 MAP Kinase Pathway in Cancer 3.3 The ERK1/2 MAP Kinase Pathway in Cancer Metastasis 3.3.1 Loss of Cellular Contacts, Detachment From the Primary Tumor and Local Invasion 3.3.1.1 The Epithelial-Mesenchymal Transition (EMT) 3.3.1.2 Extracellular Proteases and Invasiveness 3.3.1.3 Tumor Cell Motility 3.3.2 Intravasation and Dissemination to Distant Organ Sites 3.3.2.1 Intravasation 3.3.2.2 Surviving Anoikis 3.3.2.3 Escape From Immune Response 3.3.3 Extravasation, Formation of Micrometastases and Outgrowth of Secondary Tumors 3.3.3.1 Extravasation 3.3.3.2 Establishment and Outgrowth of Micrometastases Into Macrometastases 3.4 Concluding Remarks References 4 Mitogen-Activated Protein Kinase-Activated Protein Kinases and Metastasis 4.1 Introduction 4.2 MAPKAPK and Cancer 4.2.1 Mutations in the MAPKAPK-encoding Genes in Cancer Tissue 4.2.2 MAPKAPK Expression Levels in Cancers 4.2.3 MAPKAPK and Cell Cycle 4.2.4 MAPKAPK and Cell Survival 4.3 MAPKAPK and Metastasis 4.3.1 MAPKAPK and Regulation of the Cytoskeleton 4.3.1.1 HSP27 4.3.1.2 Cofilin 4.3.1.3 Arp2/3 4.3.1.4 CapZIP 4.3.1.5 Lymphocyte-Specific Protein 1 4.3.1.6 Filamin A 4.3.1.7 5-Lipoxygenase 4.3.1.8 Vimentin 4.3.1.9 Myosin 4.3.2 MAPKAPK and Gene Regulation 4.3.2.1 E-cadherin 4.3.2.2 CD44 4.3.2.3 Urokinase Plasminogen Activator 4.3.2.4 Matrix Metalloproteinases 2 and 9 4.3.2.5 Transforming Growth Factor 4.3.2.6 Chemoattractant Receptors 4.3.2.7 Human Epidermal Growth Factor Receptor 2 4.3.2.8 Cyclooxygenese-2 4.3.2.9 p75NTR 4.3.2.10 p27KIP1 4.3.2.11 p53 4.4 Role of MAPKAPK in Tumour Angiogenesis Triggered by VEGF 4.5 MAPKAPK Inhibitors 4.6 Future Perspectives References 5 Grb2 and Other Adaptor Proteins in Tumor Metastasis 5.1 Introduction 5.2 Grb2 as a Paradigm for Adaptor Proteins in Oncogenesis and Tumor Metastasis 5.2.1 The Adaptor Protein Grb2 5.2.2 Grb2 in Cancer and Tumor Metastasis 5.2.3 Targeting Grb2 5.3 Other Adaptor Proteins in Tumor Metastasis 5.3.1 Shc 5.3.2 IRS Adaptor Proteins in Mammary Tumor Metastasis 5.3.3 Other Grb Proteins in Oncogenesis and in Tumor Metastasis: Grb7, Grb10 and Grb14 5.3.4 Nck1 and 2 in Cell Motility and Invasion 5.3.5 CRK and CRKL 5.3.6 NEDD9 in Melanoma and Other Cancers 5.4 Conclusions References 6 The Role of ROS Signaling in Tumor Progression 6.1 Introduction 6.2 Generation of ROS for Triggering Tumor Metastasis 6.3 The Intracellular ROS Generation Involved in Tumor Metastasis 6.3.1 The Role of NADPH Oxidase 6.3.2 The Role of Mitochondria 6.4 The Signaling Pathway Triggered by ROS for Tumor Cell Progression 6.4.1 The Direct Signal Target of ROS 6.4.1.1 The Role of PKC 6.4.1.2 The Role of PTP 6.4.2 The Down-Stream Signal Cascades Regulated by ROS 6.4.2.1 The MAPK Cascade 6.4.2.2 The p-21 Kinase 6.5 The Transcriptional System Regulated by ROS in Tumor Progression 6.6 Expression of Genes Regulated by ROS for Tumor Progression 6.7 Involvement of ROS in Cytoskeletal Rearrangement 6.8 Prevention of Tumor Progression by Chemical and Enzymatically Antioxidant 6.9 Summary and Conclusion References 7 Signal Cross Talks for Sustained MAPK Activation and Cell Migration Mediated by Reactive Oxygen Species: The Involvement in Tumor Progression 7.1 Introduction 7.2 The Sustained MAPK Activation for Cell Migration and Invasion 7.3 The Role of Integrin Cascade in Sustained MAPK Signaling During Cell Migration and Invasion 7.4 Cooperation of Integrin Signaling with RTK and PKC to Enhance ERK Activation and Cell Migration 7.4.1 The Cross Talk of Integrin with RTK 7.4.2 The Cross Talk of Integrin with PKC for Uncontrolled Cell Migration 7.5 The Role of ROS Signal Mediating Sustained ERK Activation and Cell Migration 7.5.1 The ROS Signaling 7.5.2 Signal Amplification Triggered by ROS 7.5.3 The Proposed Molecular Mechanisms for ROS-Mediated Signal Cross Talk Between Integrin and Other Signal Cascade 7.5.3.1 ROS-Mediated Cross Talk of Integrin and RTK 7.5.3.2 ROS-Mediated Cross Talk of Integrin and PKC 7.6 Conclusion and Perspective References 8 Insights into the Dynamics of Focal AdhesionProtein Trafficking in Invasive Cancer Cells and ClinicalImplications 8.1 Introduction 8.2 Biology of Cancer Cell Migration and Invasion 8.2.1 Overview 8.2.2 The FA Signaling Network 8.2.3 Cell Motor Proteins, Proteins Traffics, and Cell Motility 8.3 Trafficking and Turnover of FA Proteins in Cancer Cells 8.4 The Rab-GTPases as Central Regulators of Protein Traffics 8.5 Deregulation of Protein Trafficking in Cancer and its Clinical Implications 8.6 Conclusion and Perspectives References 9 Notch Signaling in Cancer Metastasis 9.1 The Notch Signaling Pathway 9.2 Notch Signaling Regulates Epithelial-Mesenchymal Transition (EMT) 9.3 Notch Signaling Contributes to Tumor Cell Invasion and Adhesion 9.4 Notch Plays a Central Role in Tumor Angiogenesis 9.5 Notch Signaling Is Involved in the Tumor Cell Survival and Proliferation 9.6 The Emerging Role of Notch Signaling in Tumor Stem Cell 9.7 Summary References 10 New Concepts on the Critical Functions of Cancer- and Metastasis-Initiating Cells in Treatment Resistance and Disease Relapse: Molecular Mechanisms, Signaling Transduction Elements and Novel Targeting Therapies 10.1 Introduction 10.2 Molecular Mechanisms Associated With the Malignant Transformation of Tissue-Resident Adult Stem Cells in Cancer- and Metastasis-Initiating Cells During Cancer Initiation and Progression 10.2.1 Molecular Transforming Events in Tissue-Resident Stem/Progenitor Cells and Their Progenies Induced Through the Interplay of Diverse Growth Factors, Cytokines and Chemokines 10.2.2 Molecular Transforming Events in Cancer-Initiating Cells and Their Progenies Induced Through the EMT Process and Tumor-Associated Stromal Remodeling 10.3 Intrinsic and Acquired Phenotypes of Cancer- and Metastasis-Initiating Cells Associated With Their Resistance to Current Cancer Treatments 10.3.1 Functions of ABC Transporters and Anti-apoptotic Factors in Intrinsic and Acquired Multidrug Resistance Phenotypes of Cancer Stem/Progenitor Cells 10.4 Novel Targeted Therapies Against Aggressive and Recurrent Cancers 10.4.1 Molecular Targeting of Tumor- and Metastasis-Initiating Cells and Their Differentiated Progenies 10.4.2 Molecular Targeting of the Local Microenvironment of Tumor- and Metastasis-Initiating Cells and Their Differentiated Progenies 10.5 Conclusions and Perspectives References 11 Involvement of Lipid Rafts in Growth Factor Receptors-Mediated Signaling for Cancer Metastasis 11.1 Introduction 11.2 The Structure and Function of Lipid/Membrane Rafts 11.3 The Role of Lipid Rafts in Re-modeling of the Peri-Cellular Microenvironments for Metastasis 11.4 The Involvement of Lipid Rafts in Cell Migration 11.5 The Role of Lipid Rafts in Signal Transduction Leading to Metastasis 11.5.1 The Role of Membrane Lipid Raft in Epidermal Growth Factor Receptor (EGFR) Mediated Signaling 11.5.2 Transforming Growth Factor Beta-(TGF ) 1 Signaling 11.5.2.1 The Role of TGF Signaling in Tumor Suppression 11.5.2.2 Involvement of Lipid Raft in TGF Signaling 11.6 Conclusion and Perspective References 12 Cadherin-Catenin Signaling in Ovarian Cancer Progression 12.1 Introduction 12.1.1 Ovarian Cancer 12.1.2 Cadherins 12.2 Expression of Cadherins and Catenins in Ovarian Cancer 12.2.1 Classical Cadherins 12.2.1.1 N-cadherin 12.2.1.2 E-cadherin 12.2.1.3 P-cadherin 12.2.2 Other Cadherins 12.2.2.1 H-cadherin 12.2.2.2 VE-cadherin 12.2.2.3 Cadherin-4 12.2.2.4 Cadherin-6 12.2.2.5 Cadherin-11 12.2.3 Catenins 12.2.3.1 α-catenin 12.2.3.2 β-catenin 12.2.3.3 γ-catenin 12.2.3.4 p120ctn 12.3 Role of Cadherins and Catenins in Ovarian Cancer 12.3.1 Cell Survival 12.3.2 Differentiation 12.3.3 Motility and Invasion 12.3.4 Adhesion 12.3.5 Angiogenesis 12.4 Signaling by Cadherin-Catenin in Ovarian Cancer 12.4.1 Signaling Through -catenin 12.4.2 Signaling Through p120ctn 12.4.3 Cross-talk with Receptor Tyrosine Kinases 12.5 Regulation of Cadherin by Hormones, Growth Factors, and Cytokines- Involvement in Ovarian Tumor Progression 12.5.1 E- and N-cadherin 12.5.2 P-cadherin 12.6 Cadherins as Drug Targets 12.7 Conclusion References 13 PTP4A3, a Signal Molecule Deregulated in Uveal Melanoma Metastasis 13.1 Introduction 13.2 How to Identify Metastasis Inducing Genes? 13.3 Overexpression of PTP4A3 in Class 2 Uveal Melanoma Cells 13.4 The Role of PTP4A3 in Signal Transduction Mediating Tumor Metastasis 13.5 Conclusion References 14 Signal Transduction Pathways Involved in Hepatocarcinogenesis and Metastasis of Hepatoma 14.1 Introduction 14.1.1 Risk Factors 14.1.2 Stem Cells and Liver Function 14.1.3 Role of Stem Cells in Liver Cancer 14.2 Cellular Signaling Pathways in Liver Cancer 14.2.1 p53 Pathway 14.2.2 Retinoblastoma Pathway 14.2.3 Wnt Signaling 14.2.4 Ras Pathway 14.2.5 JAK/STAT Pathway 14.2.6 MAP Kinase Pathway 14.2.7 Stress Response Pathways 14.2.8 Growth Factors and Their Receptors 14.3 Mechanisms Involved in the Metastasis of Hepatoma 14.4 Strategies for Early Detection and Treatment of Liver Cancer 14.4.1 Gene and Protein Profiling 14.4.2 Development of Experimental Tumor Models 14.4.3 Identification of Therapeutic Targets and Novel Biomarkers 14.5 Conclusions References Index "The poor prognosis and high mortality for cancer patients are majorly ascribed to tumor metastasis, one of the most complicated pathological processes. Elucidation of molecular mechanisms for metastasis is essential for management and prevention of this lethal condition. In the book to be published, we take comprehensive review in regard with the signal mechanisms responsible for triggering a series of phenotypical changes of primary tumor which may lead to final colonization of the tumor in a second home. Specifically, the initial stage of tumor metastasis will be highlighted. The complex tumor microenvironment accumulate a lot of growth factors, inflammatory cytokines and extracellular matrix which may turn into a group of potent metastatic factors. An integrated and sustained signaling induced by these metastatic factors may trigger EMT, migration and invasion of primary tumor into surround tissue. Blockade of these signal pathways is the most effective approach for prevention of tumor metastasis. A lot of clinical trials are under way for this purpose and the outcome are promising. The expert reviews compiled in this book may encourage the researcher in this exciting field for future study."--Page 4 of cover The poor prognosis and high mortality for cancer patients are majorly ascribed to tumor metastasis, one of the most complicated pathological processes. Elucidation of molecular mechanisms for metastasis is essential for management and prevention of this lethal condition. In the book to be published, we take comprehensive review in regard with the signal mechanisms responsible for triggering a series of phenotypical changes of primary tumor which may lead to final colonization of the tumor in a second home. Specifically, the initial stage of tumor metastasis will be highlighted. The complex tumor microenvironment accumulate a lot of growth factors, inflammatory cytokines and extracellular matrix which may turn into a group of potent metastatic factors. An integrated and sustained signaling induced by these metastatic factors may trigger EMT, migration and invasion of primary tumor into surround tissue. Blokcade of these signal pathways is the most effective approach for prevention of tumor metastasis. A lot of clinical trials are under way for this purpose and the outcome are promising. The expert reviews compiled in this book may encourage the researcher in this exciting field for future study.