The Molecular Biology of Cancer A Bridge from Bench to Bedside

by Pelengaris, Stella; Khan, Michael

• ISBN13: 9781118008812
• ISBN10: 1118008812
• Edition: 2nd
• Format: Paperback
• Copyright: 2013-05-28
• Publisher: Wiley-Blackwell

Summary

 The Molecular Biology of Cancer, Stella Pelengaris & Michael Khan

 This capturing, comprehensive text, extensively revised and updated for its second edition, provides a detailed overview of the molecular mechanisms underpinning the development of cancer and its treatment.

 “Bench to Bedside”: A key strength of this book that sets it apart from general cancer biology references is the interweaving of all aspects of cancer biology from the causes, development and diagnosis through to the treatment and care of cancer patients – essential for providing a broader view of cancer and its impact.

 The highly readable presentation of a complex field, written by an international panel of researchers, specialists and practitioners, would provide an excellent text for graduate and undergraduate courses in the biology of cancer, medical students and qualified practitioners in the field preparing for higher exams, and for researchers and teachers in the field.

 For the teaching of cancer biology, special features have been included to facilitate this use: bullet points at the beginning of each chapter explaining key concepts and controversial areas; each chapter builds on concepts learned in previous chapters, with a list of key outstanding questions remaining in the field, suggestions for further reading, and questions for student review. All chapters contain text boxes that provide additional and relevant information.

 Key highlights are listed below: 

• An overview of the cancer cell and important new concepts. 

• Selected human cancers: lung, breast, colorectal, prostate, renal, skin, cervix, and hematological malignancies. 

• Key cellular processes in cancer biology including  (a) traditionally important areas such as cell cycle control, growth regulation, oncogenes and tumour suppressors apoptosis, as well as (b) more highly topical areas of apoptosis, telomeres, DNA damage and repair, cell adhesion, angiogenesis, immunity, epigenetics, and the proteasome. 

• Clinical oncology: In-depth coverage of important concepts such as screening, risk of cancer and prevention, diagnoses, managing cancer patients from start to palliative care and end-of-life pathways.
  
  
• Chapters highlighting the direct links between cancer research and clinical applications. 

•  New coverage on how cancer drugs are actually used in specific cancer patients, and how therapies are developed and tested. 

• Systems Biology and cutting edge research areas covered such as RNA interference (RNAi). 

• Each chapter includes key points, chapter summaries, text boxes, and topical references for added comprehension and review. 

• Quotations have been used in each chapter to introduce basic concepts in an entertaining way.
  
  
• Supported by a dedicated website at www.blackwellpublishing.com/pelengaris 

 We should list the great reviews we got for first edition which are on the back of the 2^nd edition:

“A capturing, comprehensive, clearly written and absolutely accurate introduction into cancer biology…..This book deserves great praise for the readable presentation of this complex field….the true synthesis of bench and bedside approaches is marvelously achieved.” Christian Schmidt, Molecular Cell

“Chapters address the issues of cancer diagnosis, treatment, and patient care and set the book apart from general molecular biology references….This book is applicable to both graduate and undergraduate students, and in the context of a research laboratory, this book would be an excellent resource as a reference guide for scientists at all levels.” V.Emuss, Institute of Cancer Research, London.

Also, from the first edition:

“Pelengaris, Khan, and the contributing authors are to be applauded. The Molecular Biology of Cancer is a comprehensive and readable presentation of the many faces of cancer from molecular mechanisms to clinical therapies and diagnostics. This book will be welcomed by neophyte students, established scientists in other fields, and curious physicians.” -Dean Felsher, Stanford University

 

Author Biography

Stella Pelengaris Ph.D is Director of Pharmalogos and previous Researcher at the Imperial Cancer Research Fund, and Senior Research Fellow at the University of Warwick and Warwick Medical School.

Mike Khan Ph.D FRCP is Associate Professor of Medicine at University Hospitals of Coventry and Warwickshire and previous Head of Molecular Medicine at the University of Warwick.

Table of Contents

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

Haploinsuffi ciency 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 modifi cations, 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