Thomas-Tikhonenko Cancer Genome and Tumor Microenvironment

1. Auflage 2010
ISBN: 978-1-4419-0711-0
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 480 Seiten

Reihe: Cancer Genetics

Oncogenes and tumor suppressor genes had been traditionally studied in the context of cell proliferation, differentiation, senescence, and survival, four relatively cell-autonomous processes. Consequently, in the late '80s-early '90s, neoplastic growth was described largely as an imbalance between net cell accumulation and loss, brought about through mutations in cancer genes. In the last ten years, a more holistic understanding of cancer has slowly emerged, stressing the importance of interactions between neoplastic and various stromal components: extracellular matrix, basement membranes, fibroblasts, endothelial cells of blood and lymphatic vessels, tumor-infiltrating lymphocytes, etc. The commonly held view is that changes in tumor microenvironment are 'soft-wired', i.e., epigenetic in nature and often reversible. Yet, there exists a large body of evidence suggesting that well-known mutations in cancer genes profoundly affect tumor milieu. In fact, these non-cell-autonomous changes might be one of the primary reasons such mutations are preserved in late-stage tumors.

Autoren/Hrsg.

Thomas-Tikhonenko, Andrei

Inhaltsverzeichnis

1;Acknowledgments;5
2;Contents;6
3;Contributors;8
4;Part I Opening Remarks;11
4.1;1 Hardwiring Tumor Progression;12
4.2;References;17
5;Part II Breaking Away: Epithelial-Mesenchymal Transition;18
5.1;2 PI3K/AKT Pathway and the Epithelial--MesenchymalTransition;19
5.1.1; Cast of Characters;19
5.1.2; Introduction;19
5.1.2.1; EMT Definition;20
5.1.2.2; EMT During Development and Cancer;21
5.1.3; IGF and EMT;22
5.1.3.1; General Functions of IGF;22
5.1.3.2; IGFs Induce EMT;23
5.1.3.3; IGF-1R and EMT;24
5.1.4; Downstream of IGFR;24
5.1.4.1; PRL-3 and EMT;24
5.1.4.2; PTEN and EMT;25
5.1.5; PI3K and AKT;25
5.1.5.1; Biochemical Mechanisms;26
5.1.5.2; General Functions of AKT;26
5.1.5.3; AKT and EMT;29
5.1.5.4; GSK3 and EMT;29
5.1.6; From AKT to NF-B;29
5.1.6.1; General Functions of NF-B;29
5.1.6.2; NF-B and EMT;30
5.1.6.3; Snail and Related Transcription Factors in EMT;30
5.1.7; E-cadherin and EMT;31
5.1.7.1; E-cadherin and Epithelial Cells;31
5.1.7.2; E-cadherin Function Is Modulated by IGF;32
5.1.7.2.1; IGF-1R Interacts Indirectly with E-cadherin and -catenin;32
5.1.7.2.2; IGFs Redistribute Proteins of Adherens Junctions;32
5.1.7.3; Other Regulators of E-cadherin;34
5.1.7.3.1; Ets-Binding Sites in the E-cadherin Promoter;34
5.1.7.3.2; E-cadherin E-boxes;34
5.1.8; Conclusions;34
5.2;References;35
5.3;3 Loss of Cadherin--Catenin Adhesion System in Invasive Cancer Cells;41
5.3.1; Cast of Characters;41
5.3.2; Introduction;41
5.3.3; Overview of CadherinCatenin Adhesion System;42
5.3.4; Loss of CadherinCatenin Adhesion System in Human Cancer and Cancer Prognosis;44
5.3.4.1; Breast Cancer;44
5.3.4.2; Gastrointestinal Cancer;45
5.3.4.3; Thyroid Cancer;46
5.3.4.4; Basal and Squamous Cell Carcinoma (BCC and SCC);46
5.3.4.5; Prostate Cancer;47
5.3.4.6; Lung Cancer;48
5.3.5; Switch from Epithelial to Mesenchymal Cadherin Expression and Its Role in Tumor Invasion;51
5.3.6; Paradoxical Re-emergence of the CadherinCatenin-Mediated Adhesion System in Metastatic Lesions;51
5.3.6.1; Causal Evidence Implicating Cadherin--Catenin System in Cancer Progression and Metastasis;52
5.3.6.2; Causal Evidence from Studies on Cell Lines In Vitro and on Xenograft Tumors;53
5.3.6.3; Evidence from Genetically Engineered Mice;53
5.3.7; CadherinCatenin Function in Cancer Progression;54
5.3.7.1; Adhesive Function of Cadherin--Catenin System as an Inhibitor of Invasion;55
5.3.7.2; Cadherin--Catenin System as Regulator of Growth Factor Receptor Signaling;55
5.3.7.3; CadherinCatenin System as a Regulator of -Catenin Signaling;57
5.3.8; Mechanisms of CadherinCatenin System Inactivation in Human Tumors;58
5.3.8.1; Inactivation of Cadherin--Catenin System by Mutations in Cadherins and Catenins;58
5.3.8.2; Inactivation of Cadherin--Catenin System by Transcriptional Repression;59
5.3.8.3; Inactivation of Cadherin--Catenin System by Post-transcriptional Regulation;60
5.3.9; Conclusions;61
5.4;References;62
5.5;4 Rho GTPases in Regulation of Cancer Cell Motility, Invasion, and Microenvironment;75
5.5.1; Cast of Characters;75
5.5.2; Introduction;75
5.5.3; Overview of Rho GTPases: Regulation and Function;76
5.5.3.1; Rho Subfamily of Small GTPases;77
5.5.4; Regulators of Rho GTPase GTP/GDP Cycling;78
5.5.4.1; Rho GTPases as Master Regulators of Actin Cytoskeletal Dynamics;80
5.5.5; Aberrations of Rho Activity in Cancer;81
5.5.5.1; Alteration of Rho GTPases in Cancer ;81
5.5.5.2; Alteration in Regulators of Rho GTPases in Cancer;82
5.5.5.3; Alteration of Rho GTPase Downstream Effectors in Cancer;83
5.5.6; Rho GTPase Contributions to Tumor Cell Motility, Invasion, and Metastasis;83
5.5.6.1; Altered Cell--Cell Adhesion;84
5.5.6.2; Altered Cell--Matrix Adhesion;86
5.5.6.3; Altered Cell Migration;87
5.5.7; Dynamic Interplay Between Rho GTPases and the Tumor Microenvironment;89
5.5.7.1; Rho GTPase Involvement in ECM Contraction as a Driving Force Behind Cancer Initiation and Invasion;89
5.5.7.2; Rho GTPase Involvement in Fibroblast-Led Invasion of Cancer Cells;91
5.5.8; Conclusions;92
5.6;References;92
5.7;5 Merlin/NF2 Tumor Suppressor andEzrin--Radixin--Moesin (ERM) Proteins in Cancer Development and Progression;100
5.7.1; Cast of characters;100
5.7.2; Introduction: Discovery, Functional Relationship, and Structural Organization;100
5.7.2.1; ERM proteins;100
5.7.2.1.1; Homology;100
5.7.2.1.2; Structure and Domain Organization;101
5.7.2.1.3; Tissue Localization and Functional Relationship;101
5.7.2.2; Merlin;103
5.7.2.2.1; Structure;103
5.7.3; Conformational Regulation;104
5.7.3.1; ERM proteins;104
5.7.3.2; Merlin;105
5.7.4; Cellular Functions;106
5.7.4.1; ERM Proteins;106
5.7.4.1.1; Membrane and Cytoskeleton Linker;106
5.7.4.1.2; Intracellular Signaling;107
5.7.4.1.3; Nuclear Localization;108
5.7.4.2; Merlin;108
5.7.4.2.1; Membrane and Cytoskeleton Linker;108
5.7.4.2.2; Stabilizing AJs and Contact-Dependent Growth Inhibition;108
5.7.4.2.3; Signaling Pathways;109
5.7.5; Physiological Function;109
5.7.5.1; ERM Proteins;109
5.7.5.1.1; Epithelial Cell Morphogenesis and Embryogenesis;109
5.7.5.1.2; Angiogenesis;110
5.7.5.1.3; T-Lymphocyte Physiology;110
5.7.5.2; Merlin;111
5.7.5.2.1; Morphogenesis;111
5.7.6; Function in Cancer Development and Progression;111
5.7.6.1; ERM Proteins;111
5.7.6.1.1; Sarcomas;112
5.7.6.1.2; Head and Neck Cancer;113
5.7.6.1.3; Melanoma;113
5.7.6.1.4; Serous Ovarian Carcinoma;113
5.7.6.1.5; Lung Adenocarcinoma;113
5.7.6.1.6; Phagocytic Activity of Ezrin;114
5.7.6.2; Merlin;114
5.7.7; Conclusions;115
5.8;References;115
6;Part III Coming Up for Air: Hypoxia and Angiogenesis;123
6.1;6 von HippelLindau Tumor Suppressor, Hypoxia-Inducible Factor-1, and Tumor Vascularization;124
6.1.1; Cast of Characters;124
6.1.2; Introduction;125
6.1.3; Renal-Cell Carcinoma;125
6.1.4; VHL Gene;126
6.1.5; VHL Protein;127
6.1.6; HIF-1;129
6.1.7; Target Genes Transcriptionally Regulated by HIF-1;130
6.1.8; Angiogenesis/Hypoxia;131
6.1.9; Anti-angiogenic Therapy;133
6.1.10; Conclusions;133
6.2;References;134
6.3;7 RAS Oncogenes and TumorVascular Interface;138
6.3.1; Cast of Characters;138
6.3.2; Introduction;139
6.3.2.1; The Link Between Oncogenes and Tumor Angiogenesis;139
6.3.3; TumorVascular Interface and Cancer Progression;140
6.3.4; Tumor Angiogenesis;141
6.3.5; Angiogenic Factors and Their Interactions;143
6.3.6;RAS Oncogenes in Cancer Progression and Angiogenesis;145
6.3.7; RAS-Dependent Multicellular Angiogenic Phenotype;147
6.3.8; Systemic Vascular Consequences of the Oncogenic Transformation;150
6.3.9; RAS, Coagulopathy, and Tumor Angiogenesis;151
6.3.10; Mechanisms of RAS-Dependent Regulation of Vascular Effectors;153
6.3.11; Redundancy of RAS-Regulated Angiogenic Pathways;155
6.3.12; RAS and the Responses of Cancer Cells to Vascular Proximity;156
6.3.13; Conclusions;157
6.4;References;158
6.5;8 Myc and Control of Tumor Neovascularization;171
6.5.1; Cast of Characters;171
6.5.2; Introduction;171
6.5.3; Deregulated Myc, Tumor Neovascularization, and the Angiogenic Balance;172
6.5.4; The Myc-VEGF Axis in Tumorigenesis;174
6.5.4.1; Myc as the Inducer of VEGF;174
6.5.4.2; Myc, Hypoxia, and VEGF;175
6.5.4.3; Myc, Normoxia, Inflammation, and VEGF;178
6.5.5; Other Ways to Flip the Switch;179
6.5.5.1; VEGF-Independent Effects of Myc;179
6.5.6; Downregulation of Thrombospondin-1 and Related Proteins by Myc;181
6.5.7; N-Myc and Angiogenesis;183
6.5.8; Conclusions;183
6.6;References;184
6.7;9 p53 and Angiogenesis;192
6.7.1; Cast of Characters;192
6.7.2; Introduction: Hardwiring the Angiogenic Switch;192
6.7.3; p53: The Guardian of the Genome;193
6.7.4; A Role for p53 in Inhibiting Angiogenesis;195
6.7.4.1; Inhibition of Hypoxia-Sensing Systems;196
6.7.4.2; Downregulation of Pro-angiogenic Factors;197
6.7.4.2.1; VEGF;198
6.7.4.2.2; COX-2;199
6.7.4.2.3; FGF2 and FGF-BP;199
6.7.4.3; Transcriptional Activation of Anti-Angiogenic Factors;200
6.7.4.3.1; Thrombospondin-1 (TSP-1 or THBS1);200
6.7.4.3.2; Brain-Specific Angiogenesis Inhibitor 1 (BAI1);201
6.7.4.3.3; Ephrin Signaling;201
6.7.4.3.4; SERPINB5/Maspin;202
6.7.4.3.5; Anti-angiogenic Collagens;202
6.7.5; Clinical implications of p53-mediated Upregulation of Endogenous Angiogenesis Inhibitors;205
6.7.5.1; Collagen-Derived Angiogenesis Inhibitors May Contribute to the Body's Natural Tumor Suppressor Mechanisms;205
6.7.5.2; Endogenous Angiogenesis Inhibitors May Mediate Long-Range Host--Tumor Interactions;206
6.7.5.3; A Potential Role for Endogenous Angiogenesis Inhibitors in Promoting Tumor Dormancy;208
6.7.6; p53-Induced Angiogenesis Inhibitors as Potential Cancer Therapeutics;208
6.7.7; The Role of p53 Status in Anti-angiogenic Therapies;210
6.7.8; Conclusions;211
6.8;References;212
6.9;10 Ink4a Locus: Beyond Cell Cycle;220
6.9.1; Cast of Characters;220
6.9.2; Introduction;220
6.9.2.1; p16 Is a Cdk Inhibitor and Tumor Suppressor;220
6.9.2.2; Mechanism of Cell Cycle Inhibition;221
6.9.3; Tumor Biology;221
6.9.3.1; Induction in Settings of Sustained Proliferation;221
6.9.3.2; The Promoter;222
6.9.3.3; Heterogeneous Expression in Tumors;222
6.9.3.4; Stem Cell Regulator?;223
6.9.4; Genetic Dissection of p16 Function In Vivo;223
6.9.4.1; Spontaneous Tumorigenesis;223
6.9.4.2; Inhibition of Tumor Progression;223
6.9.4.3; Increased Vascularity in the Absence of p16;224
6.9.4.4; Increased Long-Term Proliferative Capacity in Some p16-Null Tissues;225
6.9.5; p16 Response Pathways Revisited: Potential Non-cell-autonomous Effects;225
6.9.5.1; Repression of VEGF;226
6.9.5.2; Myc as a Target;227
6.9.5.3; COX-2 and ''Stressed'' Cells;227
6.9.5.4; Angiogenic Signaling and the Stem Cell Niche;227
6.9.6; Conclusions;227
6.10;References;228
7;Part IV Gaining New Ground: Metastasis and Stromal Cell Interactions;233
7.1;11 Nm23 as a Metastasis Inhibitor;234
7.1.1; Cast of Characters;234
7.1.2; Introduction;234
7.1.3; Nm23 Discovery and the Nm23 Gene Family;234
7.1.4; Nm23 Structure;236
7.1.5; Nm23 Promoter Characterization;236
7.1.6; Nm23 Gene Mutations;237
7.1.7; Nm23 Allelic Variations;238
7.1.8; Nm23 Sub-cellular Localization;238
7.1.9; Nm23 Expression Levels;239
7.1.10; Nm23 and Cell Cycle;240
7.1.11; Nm23 in a Mouse Model;240
7.1.12; Nm23-H1 in Various Cancers;240
7.1.12.1; Breast Cancer;242
7.1.12.2; Melanoma;242
7.1.12.3; Gall Bladder;242
7.1.12.4; Lung Cancer;242
7.1.12.5; Anal Canal Carcinoma;243
7.1.12.6; Oral Cancer;243
7.1.12.7; Astrocytoma;243
7.1.12.8; Glioma;243
7.1.12.9; Neuroblastoma;243
7.1.12.10; Bladder and Renal Cancer;244
7.1.12.11; Leukemia;244
7.1.12.12; Lymphoma;244
7.1.12.13; Meningioma;245
7.1.12.14; Nasopharyngeal Carcinoma;245
7.1.12.15; Pancreatic Cancer;245
7.1.12.16; Colorectal Carcinoma;245
7.1.12.17; Endometrial and Cervical Carcinoma;245
7.1.12.18; Ewing Tumor;246
7.1.12.19; Gastric Cancer;246
7.1.12.20; Rheumatoid Arthritis;246
7.1.12.21; Esophageal;247
7.1.12.22; Testicular Seminoma;247
7.1.12.23; Thyroid Carcinoma;247
7.1.12.24; Hepatocellular Carcinoma;247
7.1.12.25; Ovarian Carcinoma;247
7.1.12.26; Prostate Carcinoma;248
7.1.13; Nm23 Functions and Biochemical Activities;248
7.1.13.1; NDP Kinase Activity;248
7.1.14; DNase Activity;249
7.1.15; Protein Kinase or Phosphotransferase Activity;249
7.1.16; Interaction of Nm23 with Cellular Antigens;250
7.1.16.1; Association with Structural Proteins;250
7.1.16.2; Nm23 Association with Cellular Enzymes;251
7.1.16.3; Association with Transcriptional and Growth Factors;251
7.1.16.4; Nm23- and DNA-Binding Activities;253
7.1.16.5; Nm23 Association with Viral Proteins;253
7.1.17; Regulation of Nm23 Expression;253
7.1.18; Nm23 Regulates the Expression and Activity of Other Cellular Factors;254
7.1.19; Nm23-Regulated Signaling Pathways;255
7.1.20; Nm23 and Tumorigenicity;255
7.1.21; Nm23 Effects on Cell Growth and Differentiation;256
7.1.22; Nm23-H1- and Apoptosis-Related Activities;257
7.1.23; Nm23 and Tumor Metastasis;257
7.1.24; Conclusions;259
7.2;References;259
7.3;12 HGF/c-MET Signaling in Advanced Cancers;273
7.3.1; Cast of Characters;273
7.3.2; Introduction;273
7.3.3; MET Structure;274
7.3.4; HGF Structure;274
7.3.5; Biological Activity of the MET Pathway;275
7.3.6; Angiogenesis;278
7.3.7; Alterations of MET in Malignancies;279
7.3.8; Importance of MET in Lung Cancer;279
7.3.9; Head and Neck Cancer;281
7.3.10; Gastrointestinal Malignancies;281
7.3.11; Receptor Tyrosine Kinases as Therapeutic Targets;282
7.3.11.1; Inhibition of the MET Pathway as Targeted Therapy;282
7.3.12; Other Pre-clinical Targets;284
7.3.13; Conclusions;285
7.4;References;286
7.5;13 Contribution of ADAMs and ADAMTSs to Tumor Expansion and Metastasis;293
7.5.1; Cast of Characters;293
7.5.2; Introduction;293
7.5.3; Adamalysins: ADAM and ADAMTS Proteases;295
7.5.4; Prototypical Structure of ADAMs and ADAMTS;295
7.5.5; Contributions of ADAMs to Tumor Growth and Metastasis;297
7.5.6; ADAMTS and Tumor Progression;305
7.5.7; Conclusions;307
7.6;References;308
7.7;14 Stromal Cells and Tumor Milieu: PDGF et al.;315
7.7.1; Cast of Characters;315
7.7.2; Introduction;315
7.7.3; Myofibroblast Phenotype and Function;317
7.7.4; Derivation and Heterogeneity of Tumor Stromal Fibroblasts;320
7.7.5; Stromal Fibroblasts: Co-star or Supporting Actor in Tumorigenesis;321
7.7.6; Mechanisms of Tumor Promotion by TAFs;323
7.7.6.1; Tenascin-C Affects Various Aspects of Tumorigenesis;324
7.7.6.2; Serine Proteases and Their Potential Role in Generating a Reservoir of Signaling Molecules;324
7.7.6.3; A Critical Role for Growth Factors, Cytokines, and Other Soluble Factors;325
7.7.6.4; ROS and RNI: Too Much of a Good Thing is Bad;326
7.7.6.5; TAFs Pave the Way;327
7.7.7; Can the Tumor Microenvironment Lead to Transformation of Stromal Fibroblasts?;328
7.7.8; Conclusion;328
7.8;References;329
7.9;15 TGF- Signaling Alterations in Neoplastic and Stromal Cells;334
7.9.1; Cast of Characters;334
7.9.2; Introduction;334
7.9.3; TGF- Signaling;335
7.9.4; Receptor Alterations in Human Tumors;336
7.9.4.1; Changes in TGFBR2 Expression Levels and TGFBR2 Mutations in Cancer;336
7.9.4.2; TGFBR1 Mutations and Polymorphisms in Colorectal Cancer;337
7.9.5; SMAD Mutation and Isoforms in Colorectal Cancer;338
7.9.6; SMAD Antagonists;339
7.9.7; TGF- Signaling Alterations Within the Stromal Compartment;340
7.9.7.1; TGF- Signaling in Stromal Fibroblasts;340
7.9.7.2; TGF- Signaling in the Immune System;341
7.9.7.3; TGF- Signaling and EMT;342
7.9.8; Conclusions;342
7.10;References;343
8;Part V Getting Attention: Immune Recognition and Inflammation;348
8.1;16 Genetic Instability and Chronic Inflammation in Gastrointestinal Cancers;349
8.1.1; Cast of Characters;349
8.1.2; Introduction;349
8.1.3; Role of Inflammation in GI Cancer Development;350
8.1.3.1; Helicobacter pylori Gastritis and Gastric Cancer;351
8.1.3.2; Hereditary Pancreatitis and Pancreatic Cancer;351
8.1.3.3; Ulcerative Colitis and Colon Cancer Risk;352
8.1.3.4; Aspirin, NSAIDs, and Cancer Prevention;352
8.1.4; Mechanisms by Which Inflammation Promotes Carcinogenesis;353
8.1.4.1; The Role of Cytokines and Chemokines in Human Carcinogenesis;354
8.1.4.2; Eicosanoids in Inflammation and Cancer;356
8.1.4.3; DNA Damage Associated with Chronic Inflammation;357
8.1.5; Genetic Instability and DNA Repair Mechanisms;359
8.1.5.1; Chromosomal Instability in Gastrointestinal Cancers;359
8.1.6; Microsatellite Instability and DNA Mismatch Repair;361
8.1.6.1; Base Excision Repair (BER);362
8.1.6.2; DNA Methylation and Epigenetic Instability in GI Cancers;363
8.1.7; H. pylori Infection Induces an Inflammatory Microenvironment that Promotes Gastric Carcinogenesis;364
8.1.7.1; H. pylori and Gastric Cancer;364
8.1.7.2; H. pylori Strains, Bacterial Virulence Factors, and Gastric Cancer;364
8.1.7.3; Histologic Changes Associated with H. pylori Gastritis;366
8.1.7.4; Host Susceptibility and the Inflammatory Microenvironment Caused by H. pylori Infection;367
8.1.7.5; Genetic Instability in Gastric Epithelium Is Induced by H. pylori Infection;369
8.1.7.6; DNA Repair Mechanisms Protecting the Gastric Epithelium from H. pylori -Associated Cancer;370
8.1.7.7; Patterns of Gene Mutations and Epigenetic Alterations Associated with the Progression from Gastric Intestinal Metaplasia to Cancer;371
8.1.8; Ulcerative Colitis as a Paradigm for Inflammation-Associated Carcinogenesis;373
8.1.8.1; Clinical Manifestations of Ulcerative Colitis;373
8.1.8.2; The Inflammatory Microenvironment in Ulcerative Colitis;375
8.1.8.3; Molecular Pathways for the Induction of Carcinogenesis in UC;375
8.1.8.4; Genetic Instability and Molecular Alterations in Colitis-Associated Cancers;376
8.1.9; Conclusions;380
8.2;References;381
8.3;17 Immunoglobulin Gene Rearrangements, Oncogenic Translocations, B-Cell Receptor Signaling,and B Lymphomagenesis;396
8.3.1; Cast of Characters;396
8.3.2; Introduction;396
8.3.3; B-cell Development and B Lymphomagenesis;398
8.3.4; Role of the BCR in Normal B-Cell Development and B-Cell Lymphomas;399
8.3.4.1; BCR-Induced Normal B-Cell Survival;399
8.3.4.2; Requirement of BCR for B-Lymphoma Development;400
8.3.4.3; Constitutive or Tonic BCR Signaling in B-Lymphoma Maintenance;401
8.3.4.4; Role of Syk in BCR Signaling and B-Cell Development;402
8.3.4.5; Syk is Constitutively Activated in B Lymphomas and Is Critical for B-Lymphoma Survival and Proliferation;402
8.3.4.6; Role of BCR-Induced Mitogen-Activated Protein Kinases (MAPK) in B Lymphoma;403
8.3.4.6.1; JNK MAPK and Its Role in Cell Survival, Proliferation, and Apoptosis;404
8.3.4.6.2; JNK, the MAPK Which Regulates Several Downstream Effectors, Is Constitutively Activated in B Lymphomas and Is Critical for B-Lymphoma Growth;405
8.3.4.7; Transcription Factors Including Egr-1 and Pax-5 Sustain BCR Signaling in B Lymphoma;407
8.3.4.7.1; Egr-1 Is Critical for B-Lymphoma Growth;407
8.3.4.7.2; Pax-5 Is Critical for B-Lymphoma Growth;408
8.3.5; Model for Constitutive BCR Signaling and Its Implications for Basal B-Lymphoma Growth;408
8.3.6; Ligand-Dependent BCR Signaling in Lymphomagenesis;410
8.3.6.1; Infection and Lymphoma;410
8.3.6.2; Microenvironmental Regulation of B-Lymphoma Growth;411
8.3.7; Ligand-Independent BCR Signaling in Lymphomagenesis;412
8.3.8; Conclusions;414
8.4;References;414
8.5;18 Modulation of Philadelphia Chromosome-Positive Hematological Malignancies by the Bone MarrowMicroenvironment;423
8.5.1; Cast of Characters;423
8.5.2; Introduction;423
8.5.2.1; Alterations of Adhesion Molecule Expression Are Functionally Distinct in CML Chronic Phase and Blast Crisis;424
8.5.3; Diminished Adhesion Molecule Expression and Increased Migratory Capacity During the Indolent, Chronic Phase of CML (CML-CP);425
8.5.4; Enhanced Adhesion and Decreased Migratory Molecule Expression During the Aggressive, Blast Crisis Phase of CML (CML-BC);426
8.5.5; Expression of the Cadherin Family of Proteins by Diverse Cell Types;428
8.5.6; Bcr-Abl As a Contributor to Ph+ LSC Transformation: Is It Sufficient?;429
8.5.7; Tumor Stem Cells; Anatomical Organization and Origin;430
8.5.8; Competition for Space in the Niche;432
8.5.9; Microenvironment Cues and Bcr-Abl Converge on Stabilization of Tumor Cell VE-Cadherin;433
8.5.10; VE-Cadherin, Smads, and the TGF- Signaling Pathway in Hematological Tumors;435
8.5.11; Increasing the Vulnerability of Tumor Cells by Interrupting Their Connection to the Microenvironment;436
8.5.12; Conclusions;437
8.6;References;438
9;Part VI Putting It All Together;449
9.1;19 Melanoma: Mutations in Multiple Pathways at the Tumor--Stroma Interface;450
9.1.1; Cast of Characters;450
9.1.2; Introduction;450
9.1.3; The RTK/RAS/MAPK Pathway;451
9.1.3.1; Pathway Overview;451
9.1.3.2; HGF/SF;451
9.1.3.3; c-Kit Receptor;452
9.1.3.4; NRAS Mutations;454
9.1.3.5; BRAF Mutations;454
9.1.3.6; Downstream of BRAF;455
9.1.4; The PI3K/AKT Pathway;455
9.1.4.1; Pathway Overview;455
9.1.4.2; AKT Mutations;456
9.1.4.3; PTEN Mutations;456
9.1.5; Melanoma Pathways in the Context of Tumor Microenvironment;457
9.1.5.1; The IGF1/IGF-1R Axis;457
9.1.5.2; NOTCH Signaling Pathway in Melanoma;458
9.1.5.3; 3 Integrin-Mediated Effects;459
9.1.6; Conclusions;459
9.2;References;460
9.3;20 Cooperation and Cancer;465
9.3.1; Cast of Characters ;465
9.3.2; Introduction;465
9.3.3; Evolution and the Microenvironment in Cancer;465
9.3.3.1; Evolution in Cancer;465
9.3.3.2; Microenvironment in Cancer;466
9.3.3.3; Competition;467
9.3.4; Cooperation in Cancer;467
9.3.4.1; Closely Related Clones;469
9.3.4.1.1; Kin Choice;470
9.3.4.1.2; Kin Fidelity;471
9.3.4.2; Distantly Related Clones;471
9.3.4.2.1; By-Product Mutualism;472
9.3.4.2.2; Directed Reciprocity;472
9.3.4.2.3; Examples;473
9.3.5; Conclusions;475
9.3.6;References;476
10;Index;480