The Molecular Basis of Cancer

Cover......Page 1
Copyright Page......Page 2
Dedication......Page 3
List of Contributing Authors......Page 4
Preface......Page 11
1. Cancer: A Genetic Disorder......Page 13
The Discovery of Cellular Oncogenes......Page 14
The Discovery of Tumor Suppressor Genes......Page 16
Guardians of the Genome......Page 20
Immortalized Proliferation......Page 21
Nongenetic Mechanisms Accelerating Multistep Tumor Progression......Page 22
Invasive and Metastatic Behaviors......Page 23
Other Phenotypes of Neoplasia......Page 24
References......Page 25
Oncogenes......Page 27
Receptors......Page 28
Signaling Pathways of Tyrosine Kinase Receptors......Page 29
Ras and Cancer......Page 30
Functions of the MAP Kinase Pathway......Page 31
C-Myc......Page 32
PI3K–Dependent Pathways......Page 33
Cytokine Receptor Signaling......Page 34
Neurotransmitters......Page 35
Wnt Signaling......Page 36
Hedgehog/Patched Signaling......Page 37
References......Page 38
3. Tumor Suppressor Genes......Page 41
The Concept of Tumor Suppressor Genes......Page 42
The p53–Rb Pathway Interconnections......Page 43
The Interconnections of the p53 and the IGF-1–mTOR Pathways......Page 45
Conclusion......Page 47
References......Page 48
DNA Damage from Antineoplastic Therapeutic Agents......Page 49
The Six Major DNA Repair Pathways in Human Cells......Page 50
Nucleotide Excision Repair......Page 51
Examples of Redundancy in DNA Repair Pathways......Page 52
Regulation of the Six DNA Repair Pathways......Page 54
Sequential Use of Three DNA Repair Pathways to Repair DNA Cross-Links......Page 55
DNA Repair and the DNA Damage Response......Page 56
Phosphorylated Effector Proteins Assemble in DNA Damage Foci......Page 57
Fanconi Anemia: A Specific Inherited DNA Repair Defect......Page 58
Somatic Disruption of DNA Repair Pathways by Methylation and Gene Silencing......Page 59
DNA Repair Biomarkers of Gene/Protein Expression......Page 60
DNA Repair Biomarkers as Predictors of Response to Targeted Monotherapy......Page 61
BRCA1 and BRCA2......Page 62
Conclusion......Page 63
References......Page 64
The Molecular Basis for Epigenetic Control of Gene Expression......Page 66
Interplay between DNA Methylation and Chromatin in Cancer Cells......Page 68
Translational Implications of Epigenetic Changes in Cancer......Page 70
Targeting Epigenetic Abnormalities for Cancer Prevention and Therapy......Page 71
References......Page 73
History of Viral Oncology......Page 75
Virus–Host Cell Interactions......Page 77
Papillomaviruses and Cancer......Page 78
HPV and Cervical Cancer......Page 79
The Role of HPV in Cervical Cancer......Page 80
Epidermodysplasia Verruciformis......Page 82
Virus–Host Cell Interactions......Page 83
Burkitt Lymphoma......Page 84
Hodgkin Lymphoma......Page 85
Hepatitis B Virus (Virus–Host Interactions)......Page 86
HBV and Hepatocellular Carcinoma......Page 87
Hepatitis C Virus......Page 88
Human T-Cell Leukemia Viruses......Page 89
HIV, AIDS, and Cancer......Page 91
Parasites and Cancer......Page 92
References......Page 93
Epidemiology and Causal Criteria......Page 98
Smoking......Page 99
Occupation......Page 100
Types of Carcinogens......Page 101
Physical Carcinogens......Page 102
Polycyclic Aromatic Hydrocarbons......Page 103
Nitrosamines and Heterocyclic Amines......Page 104
Arsenic......Page 105
Multistage Nature of Carcinogenesis and the Multistage Model of Mouse Skin Carcinogenesis......Page 106
Initiation and Mutational Theory of Carcinogenesis......Page 107
Promotion......Page 108
Genetic Variation and Carcinogenesis......Page 109
Phase I and Phase II Biotransformation Reactions......Page 110
Aflatoxin Biotransformation......Page 112
Benzidine Biotransformation......Page 113
Glutathione S-Transferase Polymorphisms......Page 114
DNA Repair Gene Polymorphisms and Cancer Risk......Page 115
Nongenotoxic Carcinogens......Page 116
Chemoprevention......Page 117
References......Page 118
Genetic Conservation and Synteny......Page 121
Forward Genetics, Reverse Genetics, and Transgenesis......Page 122
Conditional Models......Page 124
Genetic Tools and Functional Genomics......Page 126
Cdc2 and Cdc28......Page 127
Why Use a Fly?......Page 128
Malignant Neoplastic Tumor Suppressors in Drosophila......Page 129
Fish......Page 130
Zebrafish Screen for Genomic Instability Mutants......Page 131
References......Page 132
Spontaneous and Mutagen-Induced Tumor Models......Page 134
Techniques to Modify the Mouse Genome......Page 135
Transgenic Mice......Page 136
Gene-Targeted Mice......Page 137
In Vivo Screens......Page 139
Biomarkers for Early Tumor Detection......Page 140
References......Page 141
Not a New Idea......Page 144
Testicular Cancer Follows a Cancer Stem Cell Model......Page 146
Acute Myeloid Leukemia......Page 147
Breast Cancer......Page 148
Brain Cancers......Page 149
Could Cancer Stem Cells be an Artifact of the Assays that have been Used to Identify them?......Page 150
Do Current Therapies Fail to Cure Cancer Because Cancer Stem Cells are Resistant?......Page 151
How Can We Kill Cancer Stem Cells?......Page 152
Conclusions and Future Directions......Page 153
References......Page 155
Receptors......Page 158
Protein–Protein and  Protein–Phospholipid Interactions......Page 159
Adaptors and Scaffolds......Page 160
Proteolysis and Ubiquitination......Page 161
Feedback and Cross-Talk......Page 162
Activation of Growth Factor Receptors......Page 163
Cytoplasmic Tyrosine Kinases......Page 165
The Ras-MAP Kinase Pathway......Page 166
The PI3K Pathway......Page 167
References......Page 168
The Mammalian Target of Rapamycin-1 Pathway......Page 172
PI3K/Akt Signaling, mTORC1, and Cancer......Page 174
mTORC1 and Autophagy......Page 175
Controlling Body Size......Page 176
Targeting mTOR Signaling as a Treatment for Cancer and Other Human Diseases of Cell Growth......Page 177
References......Page 178
The Cyclin-Dependent Kinases......Page 179
CDK Regulation by Small-Polypeptide Inhibitors......Page 180
Cip/Kip Family......Page 181
G1 Regulation/Restriction Point Control......Page 182
Regulation of DNA Replication (S Phase)......Page 183
The Kinases of Mitosis......Page 184
Exit from Mitosis......Page 185
SCF Ligases......Page 186
Integration of Growth-Factor Signals During G1 Phase by the Ras small GTP-Binding Protein......Page 187
Conclusion......Page 188
References......Page 189
Definitions......Page 191
Appropriate Regulation of Metabolic Pathways......Page 193
Aerobic Glycolysis: The Warburg Effect......Page 194
Glycolysis: Why Is It Good for Growth?......Page 195
High Rate of Glucose Consumption Is Needed to Maintain and Regulate Biosynthetic Pathways......Page 196
The Tricarboxylic Acid Cycle......Page 197
Tumors Use a “Truncated” Form of the TCA Cycle......Page 198
Genetic Mechanisms Behind the Metabolic Transformation in Tumors......Page 199
Activation of PI3K Pathways Clamp Cellular Metabolism in the “On” Position......Page 200
Mutation of the Tumor Suppressor LKB1 Interferes with Normal Mechanisms to Limit Growth and Proliferation......Page 202
Clinical Aspects of Tumor Metabolism......Page 203
References......Page 204
Apoptosis......Page 206
Caspases: The Executioners......Page 208
The Bcl-2 Family of Cell Death Regulators......Page 210
Nuclear Factor-kB Family......Page 211
Apoptosis-Inducing Factor......Page 212
Oncogenic Stress and p53......Page 213
Autophagy......Page 214
Receptor-Mediated Necrosis......Page 217
Exploiting Necrosis in Antitumor Immunity......Page 218
References......Page 219
Cellular Senescence: Causes......Page 222
Cellular Senescence: Control......Page 223
Cellular Senescence Suppresses Tumorigenesis In Vivo......Page 224
Cellular Senescence and Aging......Page 225
Cellular Senescence and Cancer......Page 226
References......Page 227
Tumor Microenvironment: the Coconspirator of Cancer Progression......Page 230
Macrophages Promote Tumor Progression......Page 231
Macrophages Act at Sites of Chronic Inflammation and Promote Tumor Progression......Page 232
What is a Carcinoma-Associated Fibroblast?......Page 233
Fibroblasts Stimulate Epithelial Cancer Progression Through Secreted Factors......Page 234
Transforming Growth Factor-beta Has Cancer-Promoting and -Inhibiting Effects......Page 235
Remodeling of the Tumor Microenvironment by Matrix Metalloproteinases......Page 236
Matrix Metalloproteinases Promote Carcinogenesis......Page 237
References......Page 238
18. Tumor Angiogenesis......Page 241
Vascular Development......Page 242
Critical Signaling Factors: Targets for Therapy......Page 244
Vascular Endothelial Growth Factor......Page 245
Angiopoietins/Tie Receptors......Page 246
Thrombospondin-1......Page 247
Targeting Tumor Angiogenesis in Patients......Page 248
Metronomic or “Low-Dose” Therapy......Page 249
References......Page 250
Generation of a Metastatic Cell......Page 252
Adhesion......Page 254
Matrix Degradation......Page 255
The Metastatic Cascade......Page 256
Transport......Page 257
Extravasation......Page 258
Organ Selectivity of Metastasis......Page 259
Genetic Determinants of Metastasis......Page 260
Therapeutic Challenges and Opportunities......Page 261
References......Page 262
Copy Number Aberrations......Page 264
Mutations......Page 265
Cancer Risk and Early Detection......Page 266
Therapeutic Targets......Page 267
Cytogenetics......Page 268
DNA Sequence Abnormalities......Page 269
Dideoxy Sequencing......Page 270
Whole-Genome Paired-End Shotgun Sequencing......Page 271
Single-Molecule Sequencing Methods......Page 272
Epigenome Analysis Techniques......Page 273
Microarray Epigenome Analysis......Page 274
Chromatin Immunoprecipitation Plus Microarray Analysis......Page 275
References......Page 276
Embracing the Complexity of the Cancer Transcriptome......Page 280
DNA Microarray Platforms......Page 281
Microarray Data Analysis......Page 282
Functional Annotation of Gene Expression Data......Page 283
Integrative Genomic Analysis......Page 284
Diagnosis......Page 285
Treatment......Page 286
References......Page 287
The Role of Mass Spectrometry in Proteomics......Page 289
ESI Mass Spectrometry......Page 290
Protein Profiling......Page 292
Top-Down Proteomics......Page 294
Bottom-Up Proteomics......Page 295
Protein Quantification......Page 296
Complementary Technologies......Page 298
References......Page 300
Magnetic Resonance Imaging......Page 304
Optical......Page 306
Ultrasound......Page 307
Other Imaging Modalities......Page 308
MRI Contrast Agents......Page 309
Tumor Vasculature......Page 311
Oxygen Availability......Page 313
Reporter Gene Imaging......Page 314
Imaging Pharmacokinetics of Drugs......Page 315
Molecular Imaging in Cell and Gene Therapy of Cancer......Page 316
References......Page 317
24. Bioinformatics......Page 319
General Portals......Page 320
Gene Expression Omnibus......Page 321
Analytic Tools......Page 322
Tools for End Users......Page 323
Biomedical Data Integration......Page 324
caIntegrator......Page 325
Architecture, Infrastructure, and Virtual Cancer Research Laboratories......Page 326
A Good Screening Test Versus a Suitable Cancer for Screening......Page 328
Clinical Practice......Page 330
Discovery of Novel Molecular Markers for Early Detection......Page 332
Serum Markers......Page 334
Circulating Tumor and Other Cells......Page 335
Recommendations......Page 336
Conclusion......Page 338
References......Page 339
General Concepts about the Pathogenesis of Lymphoid Malignancies......Page 341
Diffuse Large B-Cell Lymphoma......Page 344
Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissues......Page 346
Hodgkin’s Lymphoma......Page 347
Future Directions......Page 348
References......Page 349
Overview of Molecular Genetics of All......Page 350
TEL-AML1, t(12;21)(p13;q22)......Page 352
E2A-PBX1, t(1;19)(q23;p13)......Page 353
BCR-ABL, t(9;22)(q34;q11)......Page 354
T All......Page 355
c-MYC, t(8;14)(q24;q32)......Page 356
Conclusion......Page 357
References......Page 358
Anatomy and Autoregulation of the BCR-ABL Protein......Page 360
Transformation to Blast Phase......Page 362
The Challenging T315I Mutation......Page 363
Core Binding Factor Rearrangements......Page 364
PML-RARa Rearrangements......Page 365
Mixed-Lineage Leukemia Gene Rearrangements......Page 368
Mutations of the KIT Gene......Page 369
Overexpression of the BAALC and ERG Genes......Page 370
References......Page 371
Genetics and Cell Biology......Page 373
Clinical Presentation and Pathology......Page 374
Genetics and Cell Biology......Page 375
Genetics and Cell Biology......Page 376
Genetics and Cell Biology......Page 377
Genetics and Cell Biology......Page 378
Li-Fraumeni Syndrome......Page 379
Multiple Endocrine Neoplasia......Page 381
References......Page 382
Virus Infection and Lung Cancer......Page 384
EGFR Family......Page 386
MYC Family......Page 387
The 3p Tumor Suppressor Genes......Page 388
Activation of Telomerase......Page 389
Gene Expression Profiling by Microarray Technology......Page 390
Immortalized Human Bronchial Epithelial Cell Models for Studying Lung Cancer Pathogenesis......Page 391
Cancer Stem Cell Model and Lung Cancer......Page 392
References......Page 393
Histopathologic Changes in Colorectal Carcinogenesis: the Adenoma-Carcinoma Sequence......Page 395
Familial Adenomatous Polyposis......Page 396
Somatic APC Mutations in Sporadic Tumors......Page 397
Mouse Models of FAP and Genetic and Epigenetic Modifiers......Page 398
Other Forms of Intestinal Polyposis......Page 399
DNA Mismatch Repair Deficiency and Hereditary Nonpolyposis Colorectal Cancer Syndrome......Page 400
Common Somatic Alterations in Colorectal Cancer......Page 401
Inactivation of Tumor-Suppressor Genes......Page 402
Chromosome 17p and the p53 Gene......Page 403
Multistep Genetic Models of Colorectal Tumor Development......Page 404
Early Detection......Page 405
References......Page 406
Hormones......Page 408
Molecular Attributes of Breast Cancer......Page 409
Autonomy of Growth Signaling......Page 410
Reduced Apoptosis......Page 411
Future Directions......Page 412
References......Page 413
High-Grade Prostatic Intraepithelial Neoplasia......Page 415
Chromosomal Loss, Amplification, and Translocation......Page 416
Wnt Signaling and beta-Catenin......Page 417
Micro-RNA......Page 418
Estrogen Receptors......Page 419
Cell Cycle Control Genes......Page 420
PLAU......Page 421
Future Directions......Page 422
References......Page 423
34. Molecular Pathogenesis of Epithelial Ovarian Cancer......Page 425
Heterogeneity of Ovarian Cancers......Page 426
Genetic Abnormalities in Sporadic Ovarian Cancers......Page 427
Loss of Tumor-Suppressor Function......Page 428
Activation of Oncogenes......Page 431
Aberrant Signaling Pathways......Page 432
Adhesion, Invasion, Metastasis, and Angiogenesis......Page 433
Cellular Immune Response......Page 435
References......Page 436
K-ras Mutation......Page 439
Epidermal Growth Factor Receptor......Page 440
SMAD4......Page 441
Desmoplastic Reaction (Tumor Stroma)......Page 442
Cytokine Production......Page 443
References......Page 444
Production of Melanin......Page 446
Genetic Determinants of Pigmentation......Page 447
Sun Exposure......Page 449
Tumor-Suppressor Genes......Page 450
Future Directions......Page 452
References......Page 453
Clinical Description and Pathology......Page 454
Genetics and Molecular Pathogenesis......Page 455
Clinical Description and Pathology......Page 456
Clinical Description and Pathology......Page 457
Genetics and Molecular Pathogenesis......Page 458
Future Directions......Page 459
References......Page 460
Field Cancerization: Multistep Carcinogenesis Model and Chemoprevention......Page 461
Epidermal Growth Factor Receptor......Page 462
Src Tyrosine Kinase......Page 463
Phosphatase and Tensin Homologue......Page 464
Future Directions......Page 465
References......Page 466
Hereditary Syndromes and Central Nervous System Oncogenesis......Page 468
Astrocytic Tumors......Page 469
Meningioma......Page 471
Molecular Pathophysiology of Primary Central Nervous System Tumors......Page 472
References......Page 473
The Molecular Origin of Skin Tumors is Revealed by Hereditary Syndromes......Page 475
Cutaneous Cancers Arise from Multipotential Stem Cells......Page 476
Cutaneous Squamous Cell Carcinoma......Page 477
Perspective......Page 480
References......Page 481
Thyroid Tumors......Page 483
MEN1......Page 485
Hyperparathyroidism–Jaw Tumor......Page 486
Neurofibromatosis Type 1......Page 487
Pituitary Tumors......Page 488
Future Directions......Page 489
References......Page 490
Lauren’s Classification: Diffuse or Intestinal or it Does not Matter?......Page 491
E. Cadherin and the WNT Pathway: Implications in the Development of Diffuse and Intestinal Gastric Cancer......Page 492
Helicobacter Pylori–Associated Noncardia and Cardia Gastric Cancer......Page 493
Gastric Cancer and Bone Marrow–Derived Stem Cells......Page 494
Molecular Targets in Development for Gastroesophageal Cancer Treatments......Page 495
References......Page 496
Achieving Personalized Medicine......Page 498
Functional Genomic Screening......Page 499
Computational Cancer Biology......Page 500
Small-Molecule Drug Discovery......Page 501
Gene Therapy......Page 502
Pharmacokinetics......Page 503
Microdosing......Page 504
Conclusion......Page 505
References......Page 506
Molecular Targets for Cancer Treatment: Implications for Drug Discovery......Page 508
Process of Drug Screening and Discovery......Page 509
Cell-Free Screening......Page 510
Cell-Based Screening......Page 512
Screen Validation and Criteria for a Valuable Screen......Page 513
References......Page 514
45. Animal Models to Predict Anticancer Efficacy......Page 516
References......Page 521
Clearance......Page 523
Pharmacokinetics: Benefits for Individual Patients......Page 524
Pharmacodynamics......Page 525
Pharmacogenetics......Page 526
References......Page 528
Single Ascending Dose......Page 529
Drug/Food Metabolic Interaction Studies......Page 530
Combination Studies......Page 531
Modifications to Traditional Design......Page 532
Pharmacokinetically Guided Dose-Escalation Method......Page 533
Statistical Considerations of Phase 1 Studies......Page 534
Quantitative Analysis of Pharmacodynamic Markers in Tissues......Page 535
ZD1839......Page 537
Ps-341......Page 539
Imaging Techniques in Phase 1 Studies......Page 540
Conclusion......Page 543
References......Page 544
Molecular Basis of the Therapeutic Index......Page 547
Sex Hormones......Page 548
Vascular Endothelial Growth Factor......Page 550
Epidermal Growth Factor Receptor Family......Page 551
Drugs That Alter Nucleic Acid Synthesis and Function......Page 552
Inhibitors of DNA Topoisomerase......Page 553
Vinca Alkaloids and Taxanes......Page 554
Drugs Affecting Microtubule Depolymerization......Page 555
References......Page 556
Drug Sanctuary Sites (Central Nervous System and Testis)......Page 558
Genetics of Drug Resistance......Page 559
Drug Efflux Transporters......Page 560
Mutation or Altered Expression of Molecular Targets......Page 561
Enhanced DNA Repair......Page 563
Altered Pathways for Programmed Cell Death (Apoptosis)......Page 564
References......Page 565
DNA as the Target......Page 568
Mechanisms of Radiation-Induced Cell Death: The Role of Long-Term Clonogenic Assays......Page 570
Cytokines, Growth Factors, and Signaling Pathways......Page 572
Environmental Interactions......Page 573
Intrinsic Radiation Factors......Page 574
Growth Factors......Page 575
Conclusion......Page 576
References......Page 577
GM-CSF: Clinical Trials/Applications......Page 580
G-CSF: Clinical Trials/Applications......Page 582
TPO: Clinical Trials/Applications......Page 584
IL-3: Clinical Trials/Applications......Page 587
Interleukin-7......Page 588
Interleukin-12......Page 589
Interleukin-19......Page 590
Interleukin-27......Page 591
References......Page 592
Interferon Genes, Proteins, and Their Induction......Page 595
IFN Receptors and Signaling......Page 597
Inhibition of Action and Molecular Oncogenesis......Page 598
Antigrowth/Apoptosis Effects......Page 599
Immune Effects......Page 601
Antitumor Effects in Humans......Page 602
References......Page 603
53. Cancer and the Cellular Immune Response......Page 608
Dendritic Cells Link Innate and Adaptive Immunity......Page 609
Targeting TLRs on DCs to Induce Effective Antitumor Immunity......Page 611
Evidence of Immune Regulation in Melanoma......Page 613
Relationship Between Vitiligo and Response to IL-2 in Melanoma Patients......Page 614
Cytokine Therapy of Cancer......Page 615
Adoptive Immunotherapy of Cancer......Page 616
References......Page 619
54. Cancer-Specific Vaccines......Page 621
Tumor Antigens......Page 622
Principles of Cancer Vaccine Design......Page 623
Enhancement of Signal-1......Page 624
Enhancement of Signal 2: Costimulation......Page 625
Overview......Page 626
Insertion of Genes Encoding Costimulatory B7 Family Members into Tumors......Page 628
GM-CSF Gene-Transduced Tumor Vaccines......Page 629
Clinical Development of GM-CSF–Transduced Tumor Vaccines......Page 630
Peptide Vaccines......Page 631
Ex Vivo–Loaded Dendritic Cell Vaccines......Page 632
Heat shock Protein–Based Vaccines......Page 633
Engineered Bacteria......Page 634
Enhancement of Cancer Vaccine Potency with Monoclonal Antibodies That Enhance Costimulation or Block Immunologic Checkpoints......Page 635
References......Page 636
Background......Page 642
Approved Antibody Compounds......Page 644
Investigational Antibody Compounds......Page 645
References......Page 647
Killing Cancer Cells by Gene Replacement and Gene Knock-Out......Page 650
Killing Cancer Cells by Delivering Toxic Genes......Page 651
Naturally Occurring Virus That Replicate in Cancer Cells Selectively......Page 652
Viruses Engineered to Replicate Selectively......Page 653
Preclinical Development......Page 654
Safety and Toxicity......Page 656
Conclusion and Future Prospects......Page 657
References......Page 658
Cancer as a Genetic Disease of Protein-Coding Genes and Noncoding RNAs......Page 662
Ribozymes......Page 664
siRNAs and shRNAs......Page 665
ASOs/AMOs Anti-miRNAs, LNAs Anti-miRNAs, and Antagomirs......Page 666
In the Search of the Right Way and the Right Type of Delivery......Page 667
A Strategy for Using RNA as Therapeutic Molecules......Page 668
References......Page 669
HSP90: A Chaperone of Oncogenes......Page 671
Hsp90 Inhibitors Target Mutated and Chimeric Proteins Uniquely Expressed in Certain Cancers......Page 673
Hsp90 Inhibitors Exert Anti-angiogenic Activity......Page 674
The Proteasome as An Anticancer Molecular Target......Page 675
Combined Inhibition of Hsp90 and the Proteasome......Page 676
Why Are Tumor Cells Uniquely Sensitive to Hsp90 Inhibition and Proteasome Inhibition?......Page 677
References......Page 678
Prevention–Therapy Convergence......Page 681
EGFR Signaling......Page 682
PI3K/Akt Signaling......Page 683
Biomarker Cancer Risk Models......Page 684
SERMs and Aromatase Inhibitors......Page 685
Vaccines......Page 687
References......Page 688
Index......Page 691