Contributors vii
Preface to the Second Edition ix
Reviews of the First Edition x
Acknowledgments and Dedication xi
About the Companion Website xii
Introduction 1
1 Overview of Cancer Biology 3
Michael Khan and Stella Pelengaris
Introduction 5
Cancer incidence and epidemiology 8
Towards a definition of cancer 8
Causes of cancer 16
Cancer is a genetic disease 21
Cancers (and Darwin's finches) evolve by mutation and natural selection 21
Blame the parents - inherited single gene defects and susceptibility to cancer 21
The cancer "roadmap" - What kinds of genes are epimutated in cancer? 23
Viruses and the beginnings of cancer biology 25
Hens and teeth or bears and woods? The hens have it - cancer is rare 25
The barriers to cancer 25
What is the secret of cancer developme "timing" 28
Location location location - the cancer environment: nanny or spartan state 28
Cancer goes agricultural 29
Cancer superhighways - blood vessels and lymphatics 31
On your bike and turn the lights off before you go 31
Catching cancer 31
Hammering the hallmarks 32
Painting a portrait of cancer 33
The drugs don't work 34
Mechanism of origin rather than cell of origin - towards a new functional taxonomy of cancer 35
Is it worth it? 36
Conclusions and future directions 36
Bibliography 37
Appendix 1.1 History of cancer 40
2 The Burden of Cancer 43
William P. Steward and Anne L. Thomas
Introduction 43
Lung cancer 45
Breast cancer 49
Colorectal cancer 53
Carcinoma of the prostate 56
Renal carcinoma 57
Skin cancer 58
Carcinoma of the cervix 60
Hematological malignancies 60
Conclusions and future directions 63
Outstanding questions 63
Bibliography 64
Questions for student review 66
3 Nature and Nurture in Oncogenesis 67
Michael Khan and Stella Pelengaris
Introduction 69
Risk factors 73
Preventing cancers 76
Cancer genetics - in depth 78
Cancer genomics 87
Gene-environment interactions 89
Mutations and treatment 89
Chemoprevention of cancer 90
Risk factors act in combination 90
Environmental causes of cancer 93
The clinical staging and histological examination of cancer 101
Screening and biomarkers 102
Somatic gene mutations epigenetic alterations and multistage tumorigenesis 105
Conclusions and future directions 107
Outstanding questions 107
Bibliography 107
Questions for student review 109
4 DNA Replication and the Cell Cycle 111
Stella Pelengaris and Michael Khan
Introduction 112
The cell cycle - overview 114
Phases of the cell cycle 120
The cell-cycle engine: cyclins and kinases 123
Regulation by degradation 126
Regulation by transcription 129
MicroRNAs and the cell cycle 131
Chromatin 131
DNA replication and mitosis 131
Checkpoints - putting breaks on the cell-cycle engine 135
The DNA damage response (DDR) 136
The checkpoints 136
Cell-cycle entry and its control by extracellular signals 138
Changes in global gene expression during the cell cycle 139
Cell cycle and cancer 139
Drugging the cell cycle in cancer therapies 141
Conclusions and future directions 142
Outstanding questions 143
Bibliography 143
Questions for student review 144
5 Growth Signaling Pathways and the New Era of Targeted Treatment of Cancer 146
Stella Pelengaris and Michael Khan
Introduction 147
Growth factor regulation of the cell cycle 150
Growth homeostasis and tissue repair and regeneration 151
Regulated and deregulated growth 155
Cellular differentiation 157
Tissue growth and the "angiogenic switch" 158
Cancers and nutrients 158
Growth factor signaling pathways 160
A detailed description of signal transduction pathways and their subversion in cancer 160
Translational control and growth 184
Conclusions and future directions 185
Outstanding questions 185
Bibliography 186
Questions for student review 187
6 Oncogenes 188
Stella Pelengaris and Michael Khan
Introduction 189
The oncogenes 189
The discovery of oncogenes ushers in the new era of the molecular biology of cancer 191
Overview of oncogenes 191
Types of oncogenes 193
Oncogene collaboration - from cell culture to animal models 199
The c-MYC oncogene 199
The RAS superfamily 213
SRC - the oldest oncogene 228
BCR-ABL and the Philadelphia chromosome 232
The BCL-2 family 235
Biologically targeted therapies in cancer and the concept of "oncogene addiction" 235
Conclusions and future directions 235
Outstanding questions 236
Bibliography 236
Questions for student review 238
7 Tumor Suppressors 239
Martine F. Roussel
Introduction 239
The "two-hits" hypothesis: loss of heterozygosity (loh) 240
Haploinsufficiency in cancer 240
Epigenetic events 242
Definition of a tumor suppressor 242
The retinoblastoma protein family 242
p53/TP53 250
INK4a/ARF 254
The p53 and RB pathways in cancer 257
Senescence and immortalization: Role of RB and p53 258
Tumor suppressors and the control of cell proliferation 258
Tumor suppressors and control of the DNA damage response and genomic stability 260
The microRNAs and tumor suppressors 260
Conclusions and future directions 263
Acknowledgments 263
Outstanding questions 264
Bibliography 264
Questions for student review 265
8 Cell Death 266
Stella Pelengaris and Michael Khan
Introduction 267
An historical perspective 267
Apoptosis in context 267
Apoptosis as a barrier to cancer formation 271
Apoptosis versus necrosis 271
Cell death by necrosis - not just inflammatory 272
The pathways to apoptosis 272
The apoptosome - "wheel of death" 274
Caspases - the initiators and executioners of apoptosis 274
The IAP family - inhibitors of apoptosis and much more 276
The central role of MOMP and its regulators in apoptosis - the BCL-2 family 279
Mitochondrial outer membrane permeabilization (momp) 281
Endoplasmic reticulum stress 282
Stress-inducible heat shock proteins 282
Tumor suppressor p53 282
Oncogenic stress: MYC-induced apoptosis 283
Autophagy - a different kind of cell death and survival 287
Cell death in response to cancer therapy 290
Exploiting cell death (and senescence) in cancer control 290
Conclusions and future directions 292
Outstanding questions 293
Bibliography 293
Questions for student review 294
9 Senescence Telomeres and Cancer Stem Cells 295
Maria A. Blasco and Michael Khan
Introduction 296
Senescence 298
Conclusions and future directions 310
Outstanding questions 310
Bibliography 311
Questions for student review 312
10 Genetic Instability Chromosomes and Repair 314
Michael Khan
Introduction 316
Telomere attrition and genomic instability 321
Sensing DNA damage 323
Repairing DNA damage 325
Checkpoints 336
Microsatellites and minisatellites 343
Chaperones and genomic instability 344
Cancer susceptibility syndromes involving genetic instability 345
Genomic instability and colon cancer 346
Conclusions and future directions 346
Outstanding questions 347
Bibliography 347
Questions for student review 349
11 There Is More to Cancer than Genetics: Regulation of Gene and Protein Expression by Epigenetic Factors Small Regulatory RNAs and Protein Stability 350
Stella Pelengaris and Michael Khan
Introduction 351
The language of epigenetics 353
Epigenetics 353
Methylation of DNA 359
Acetylation of histones and other posttranslational modifications 360
Epigenetics and cancer 362
CIMP and MIN and the "mutator phenotype" 365
Imprinting and loss of imprinting 366
Clinical use of epigenetics 367
Regulation of translation 368
Noncoding RNA and RNA interference 369
Therapeutic and research potential of RNAi 371
Treatments based on miRNA 373
Regulating the proteins 373
Therapeutic inhibition of the proteasome 376
Receptor degradation 377
Wrestling with protein transit - the role of SUMO and the promyelocytic leukemia (PML) body 377
Conclusions and future directions 380
Outstanding questions 380
Bibliography 381
Questions for student review 382
12 Cell Adhesion in Cancer 383
Charles H. Streuli
Introduction 383
Adhesive interactions with the extracellular matrix 384
Cell-cell interactions 393
Critical steps in the dissemination of metastases 395
E-cadherin downregulation in cancer leads to migration 399
Epithelial-mesenchymal transitions 401
Integrins metalloproteinases and cell invasion 402
Survival in an inappropriate environment 404
Conclusions 406
Outstanding questions 406
Bibliography 407
Questions for student review 409
13 Tumor Immunity and Immunotherapy 410
Cassian Yee
Introduction 410
Endogenous immune response 411
Effector cells in tumor immunity 413
Tumor antigens 417
Antigen-specific therapy of cancer 420
Clinical trials in vaccine therapy 422
Cytokine therapy of cancer 423
Tumor immune evasion 424
Clinical trials in immunomodulatory therapy 425
Conclusions 425
Bibliography 426
Questions for student review 427
14 Tumor Angiogenesis 429
Christiana Ruhrberg
Introduction 429
General principles of new vessel growth 430
Pathological neovascularization: tumor vessels 430
Basic concepts in tumor angiogenesis: the angiogenic switch 432
Vascular growth and differentiation factors: stimulators of the angiogenic switch 432
Role of inhibitors in angiogenesis 436
Clinical outcomes and future directions 436
Acknowledgments 437
Bibliography 437
Questions for student review 437
15 Cancer Chemistry: Designing New Drugs for Cancer Treatment 438
Ana M. Pizarro and Peter J. Sadler
Introduction 439
Historical perspective 439
The drug discovery process and preclinical development of a drug 442
Questions remaining 457
Conclusions and future directions 457
Bibliography 458
Questions for student review 459
16 Biologically Targeted Agents from Bench to Bedside 461
Michael Khan Peter Sadler Ana M. Pizarro and Stella Pelengaris
Introduction 463
Targeted therapies 465
Cancer cell heterogeneity 466
Finding the molecular targets 468
Tumor regression in mice by inactivating single oncogenes 468
Targeted cancer therapies 473
Targeting oncogenes to treat cancer? 473
The concept of synthetic lethality and collateral vulnerability 475
Clinical progress in biological and molecular targeted therapies 476
Molecular targeted drugs - an inventory 479
DNA damage responses 490
Transcription factors 491
Targeting epigenetic regulation of gene expression 492
Hitting the extrinsic support network and preventing spread 493
Gene therapy antisense and siRNA 495
Resistance to targeted therapies - intrinsic resistance and emergence of secondary pathways and tumor escape 497
Negative feedback loops and failure of targeted therapies 500
Biomarkers to identify optimal treatments and tailored therapies 501
Pharmacogenetics and pharmacogenomics 505
Clinical trials in cancer 506
Conclusions and future directions 506
Bibliography 507
Questions for student review 508
17 The Diagnosis of Cancer 509
Anne L. Thomas Bruno Morgan and William P. Steward
Introduction 509
Clinical manifestations 510
Investigations in oncological practice 511
Non-invasive imaging techniques 516
Future novel uses of imaging 521
Proteomics and microarrays 523
Circulating tumor cells 523
Disease staging 523
Conclusions and future directions 524
Bibliography 524
Questions for student review 525
18 Treatment of Cancer: Chemotherapy and Radiotherapy 526
Anne L. Thomas J.P. Sage and William P. Steward
Introduction 526
Radiotherapy physics 526
Radiobiology 527
Treatment planning 528
Recent advances 529
Chemoradiation 530
Conclusion 540
Bibliography 542
Questions for student review 543
19 Caring for the Cancer Patient 544
Nicky Rudd and Esther Waterhouse
Introduction 544
Key concepts 544
Communication with the cancer patient 544
When is palliative care appropriate for cancer patients? 545
Palliative care assessment 545
Symptom control 545
Respiratory symptoms 547
Nausea and vomiting 547
Bowel obstruction 548
Constipation 549
Fatigue 549
Cachexia and anorexia 549
Psychological problems 549
The dying patient 550
Supportive care 550
An example of the care of a cancer patient 551
Questions remaining 551
Conclusions and future directions 551
Underlying problems 551
Comment 551
Underlying problems 552
Bibliography 552
Questions for student review 553
20 Systems Biology of Cancer 554
Walter Schubert Norbert C.J. de Wit and Peter Walden
Introduction 556
Information flow in cells 556
Model organisms and cancer models 557
Array-based technologies: genomics epigenomics and transcriptomics 559
SNPs the HapMap and the identification of cancer genes 559
Cancer mRNA expression analysis 562
CGH arrays CpG island microarrays and ChIP-on-Chip 564
Next-generation sequencing 564
Proteomics 566
Posttranslational modifications 567
Protein complexes and cellular networks 569
Clinical applications of proteomics 570
Toponomics: investigating the protein network code of cells and tissues 571
Processing the images from the cyclical imaging procedures 571
Structure code and semantics of the toponome: a high-dimensional combinatorial problem 573
Detecting a cell surface protein network code: lessons from a tumor cell 575
The molecular face of cells in diseases 576
Individualized medicine and tailored therapies 576
Discussion and conclusion 579
Bibliography 579
Internet resources 581
Questions for student review 582
Appendix 20.1 Techniques for the generation of genetically altered mouse models of cancer 582
Glossary 585
Answers to Questions 597
Index 603
