Molecular biology of human cancers : an advanced student's textbook

Preface: How to read this book………………………………………………... xiii Acknowledgements ……………………………………………………………. xvii 1 An Introduction to Human Cancers..................................................................... 1 1.1 An overview of the cancer problem .................................................................. 1 1.2 Causes of cancer............................................................................................... 5 Box 1.1 Reactive oxygen species ........................................................................ 10 1.3 Characteristic Properties of Cancers and Cancer Cells................................ 11 Box 1.2: Hallmarks of Cancer ............................................................................. 18 1.4 Characterization and Classification of Cancers in the Clinic ....................... 17 1.5 Treatment of Cancer....................................................................................... 21 Further reading..................................................................................................... 23 2 Tumor Genetics .................................................................................................... 25 2.1 Cancer as a genetic disease............................................................................ 26 2.2. Genetic alterations in cancer cells ................................................................ 27 2.3 Inherited predisposition to cancer.................................................................. 37 2.4 Cancer genes .................................................................................................. 42 2.5 Accumulation of genetic and epigenetic changes in human cancers ............. 44 Further reading..................................................................................................... 45 Box 2.1 Tumor viruses in human cancers ........................................................... 46 3 DNA Damage and DNA Repair .......................................................................... 47 3.1 DNA damage during replication: base excision and nucleotide excision repair.............................................................................................................. 48 3.2 Nucleotide excision repair and crosslink repair ............................................ 55 3.3 Strand-break repair ........................................................................................ 62 3.4 Defects in DNA repair and cancer susceptibility ........................................... 66 3.5 Cell protection mechanisms in cancer............................................................ 68 Further reading..................................................................................................... 70 4 Oncogenes.............................................................................................................. 71 4.1 Retroviral oncogenes ...................................................................................... 72 4.2 Slow-acting transforming retroviruses........................................................... 75 4.3 Approaches to the identification of human oncogenes................................... 78 4.4 Functions of human oncogenes ...................................................................... 84 Further reading..................................................................................................... 89 Box 4.1 Carcinogenesis by HTLV-I.................................................................... 90 5 Tumor Suppressor Genes .................................................................................... 91 5.1 Tumor suppressor genes in hereditary cancers.............................................. 92 5.2 RB1 and the cell cycle..................................................................................... 97 5.3 TP53 as a different kind of tumor suppressor .............................................. 101 vii 5.4 Classification of tumor suppressor genes..................................................... 109 Further reading................................................................................................... 111 Box 5.1 Human papilloma viruses..................................................................... 112 6 Cancer Pathways ................................................................................................ 113 6.1 Cancer Pathways .......................................................................................... 114 6.2 MAPK signaling as a cancer pathway ......................................................... 115 6.3 The PI3K pathway ........................................................................................ 119 6.4 Regulation of the cell cycle by the MAPK and PI3K pathways ................... 123 6.5 Modulators of the MAPK and PI3K pathways ............................................. 126 6.6 The TP53 network......................................................................................... 129 6.7 Signaling by TGF???? factors .......................................................................... 131 6.8 Signaling through STAT factors ................................................................... 132 6.9 The NF????B pathway ....................................................................................... 135 6.10 Developmental regulatory systems as cancer pathways ............................ 137 Further reading................................................................................................... 144 7 Apoptosis and Replicative Senescence in Cancer............................................ 145 7.1 Limits to cell proliferation ............................................................................ 146 7.2 Mechanisms of apoptosis.............................................................................. 150 7.3 Mechanisms of diminished apoptosis in cancer ........................................... 156 7.4 Replicative senescence and its disturbances in human cancers................... 159 Further reading................................................................................................... 164 Box 7.1: Human aging and cancer..................................................................... 165 8 Cancer Epigenetics ............................................................................................. 167 8.1 Mechanisms of epigenetic inheritance ......................................................... 168 8.2 Imprinting and X-inactivation ...................................................................... 170 8.3 DNA methylation .......................................................................................... 174 8.4 Chromatin structure...................................................................................... 179 8.5 Epigenetics of cell differentiation................................................................. 182 8.6 Epigenetics of tissue homeostasis................................................................. 185 Further reading................................................................................................... 191 Box 8.1 Carcinogenesis by HIV 192 9 Invasion and metastasis ..................................................................................... 193 9.1 Invasion and metastasis as multistep processes........................................... 194 9.2 Genes and proteins involved in cell-to-cell and cell-matrix adhesion......... 197 9.3 Genes and proteins involved in extracellular matrix remodeling during tumor invasion ................................................................................. 202 9.4 Angiogenesis ................................................................................................. 206 9.5 Interactions of invasive tumors with the immune system ............................. 210 9.6 The importance of tumor-stroma interactions.............................................. 212 Further reading................................................................................................... 216 Box 9.1 Tumor hypoxia and its consequences .................................................. 217 10 Leukemias and Lymphomas............................................................................ 219 10.1 Common properties of hematological cancers........................................... 221 10.2 Genetic aberrations in leukemias and lymphomas..................................... 223 10.3 Molecular biology of Burkitt lymphoma..................................................... 226 10.4 Molecular biology of CML ......................................................................... 232 10.5 Molecular biology of PML ......................................................................... 237 Further reading................................................................................................... 242 11 Wilms Tumor (nephroblastoma) .................................................................... 243 11.1 Histology, etiology and clinical behavior of Wilms tumors ....................... 244 11.2 Genetics of Wilms tumors and the WT1 gene............................................. 246 11.3 Epigenetics of Wilms tumors and the ‘WT2’ locus..................................... 250 11.4 Towards an improved classification of Wilms tumors ............................... 252 Further reading................................................................................................... 253 12 Cancers of the skin ........................................................................................... 255 12.1 Carcinogenesis in the skin .......................................................................... 256 12.2 Squamous cell carcinoma........................................................................... 260 12.3 Basal Cell Carcinoma................................................................................. 262 12.4 Melanoma ................................................................................................... 266 12.5 Tumor antigens ........................................................................................... 269 Further reading................................................................................................... 270 13 Colon Cancer .................................................................................................... 271 13. 1 Natural history of colorectal cancer ......................................................... 272 13.2 Familial Adenomatous Polyposis Coli and the WNT pathway .................. 273 13.3 Progression of Colon Cancer and the Multi-Step Model of Tumorigenesis .......................................................................................... 280 13.4 Hereditary nonpolyposis colon carcinoma ................................................ 282 13.5 Genomic instability in colon carcinoma..................................................... 284 13.6 Inflammation and colon cancer.................................................................. 285 Further reading................................................................................................... 287 Box 13.1 Positional cloning of tumor suppressor genes in hereditary cancers . 288 14 Bladder Cancer................................................................................................. 289 14.1 Histology and etiology of bladder cancer .................................................. 290 14.2 Molecular alterations in invasive bladder cancers .................................... 297 14.3 Molecular alterations in papillary bladder cancers .................................. 302 14.4 A comparison of bladder cancer subtypes.................................................. 304 Further reading................................................................................................... 305 Box 14.1: Tumor suppressor candidates at 9q in bladder cancer ...................... 306 15 Renal Cell Carcinoma...................................................................................... 307 15.1 The diversity of renal cancers .................................................................... 308 15.2 Cytogenetics of renal cell carcinomas........................................................ 310 15.3 Molecular biology of inherited kidney cancers .......................................... 311 15.4 Von-Hippel-Lindau syndrome and renal carcinoma.................................. 316 15.5 Molecular biology of clear cell renal carcinoma....................................... 321 15.6 Chemotherapy and immunotherapy of renal carcinomas .......................... 324 Further reading................................................................................................... 326 16 Liver Cancer ..................................................................................................... 327 16.1 Etiology of liver cancer .............................................................................. 328 16.2 Genetic changes in hepatocellular carcinoma ........................................... 331 16.3 Viruses in HCC........................................................................................... 336 Further reading................................................................................................... 339 Box 16.1 Hepatocellular carcinoma in experimental animals........................... 340 17 Stomach Cancer................................................................................................ 341 17.1 Etiology of stomach cancer ........................................................................ 342 17.2 Molecular mechanisms in gastric cancer................................................... 345 17.3 Helicobacter pylori and stomach cancer.................................................... 348 Further reading................................................................................................... 354 Box 17.1: Barrett esophagus and esophageal cancer......................................... 355 18 Breast Cancer.................................................................................................... 357 18.1 Breast biology............................................................................................. 358 18.2 Etiology of breast cancer............................................................................ 364 18.3 Hereditary breast cancer............................................................................ 365 18.4 Estrogen receptors and ERBB proteins in breast cancer........................... 373 18.5 Classification of breast cancers ................................................................. 378 Further reading:.................................................................................................. 382 19 Prostate Cancer ................................................................................................ 383 19.1 Epidemiology of prostate cancer................................................................ 384 19.2 Androgens in prostate cancer..................................................................... 389 19.3 Genetics and epigenetics of prostate cancer .............................................. 394 19.4 Tumor-stroma interactions in prostate cancer........................................... 398 Further reading................................................................................................... 402 PART III - PREVENTION, DIAGNOSIS, AND THERAPY 20 Cancer Prevention ............................................................................................ 403 20.1 The importance of cancer prevention......................................................... 403 20.2 Primary prevention..................................................................................... 404 20.3 Cancer prevention and diet ........................................................................ 408 20.4 Prevention of cancers in groups at high risk.............................................. 415 20.5 Prevention of prostate cancer by screening the aging male population.... 420 20.6 Other types of prevention ........................................................................... 423 Further reading................................................................................................... 426 21 Cancer Diagnosis .............................................................................................. 427 21.1 The evolving scope of molecular diagnostics ............................................. 427 21.2 Molecular diagnosis of hematological cancers.......................................... 429 21.3 Molecular detection of carcinomas ............................................................ 433 21.4 Molecular classification of carcinomas ..................................................... 439 21.5 Prospects of molecular diagnostics in the age of individualized therapy.. 442 Further reading................................................................................................... 447 22 Cancer Therapy ................................................................................................ 449 22.1 Limitations of current cancer therapies ..................................................... 449 22.2 Molecular mechanisms of cancer chemotherapy ....................................... 450 22.3 Principles of targeted drug therapy............................................................ 459 22.4 Examples of new target-directed drug therapies........................................ 464 22.5 New concepts in cancer therapy: Immunotherapy ..................................... 475 22.6 New concepts in cancer therapy: Gene therapy......................................... 479 22.7 The future of cancer therapy ...................................................................... 486 KEYWORD INDEX .............................................................................................489