Origin of Cancers (eBook)

Preface 6
Contents 12
Chapter 1: Introduction 20
Chapter 2: Cancer Myths 25
Introduction 26
Stem-Cell Origin of Cancers 26
Dedifferentiation of Cancer 27
Magic Bullets 27
Multistep Carcinogenesis 29
Cancer Signatures 31
Epithelial-to-Mesenchymal Transition 31
Gene Therapy 32
Cancer Vaccine 32
“Hypothesis-Generating” Research 33
“Translational” Research 33
Technologic vs. Scientific Breakthroughs 34
Curing Cancer 35
Conclusion 36
References 36
Chapter 3: History of Cancer 37
Introduction 37
Paleo-oncology 38
Civilization vs. Age 39
Written Evidence 40
Brief History of Cancer 42
History of the Stem-Cell Theory 43
Saint Peregrine 45
War on Cancer 46
Conclusion 46
References 47
Chapter 4: Origin of Cancer 50
Introduction 50
Cancer Statistics 51
Origin of Cancer 51
Theoretical Oncologists 52
Oncogenes 53
The “Two-Hit” Hypothesis 53
Initiation and Promotion 53
Multistep Carcinogenesis 54
Origins of Cancer, Revisited 55
Stem-Cell Origin of Cancers 56
Defining Idea 57
Conclusion 58
References 58
Chapter 5: Stem Cells 59
Précis 59
Introduction 59
Meristem Cells 60
Regeneration 60
The Cell Concept 61
Finding Stem Cells 61
The Nature of Stem Cells 62
Stemness 62
The Question of Stemness 64
The Stemness Within 64
Parthenogenesis 65
Beyond Stemness 65
Cloning 66
Reprogramming 66
Unknown Unknowns 68
Portrait of a Stem Cell 68
Conclusion 69
References 70
Chapter 6: Stem Cells and Cancer 71
Introduction 72
A Tale of Two Cells 72
Plight of the Tasmanian Devil 72
Secondary Malignancy 74
Stem-Cell Therapy 75
Chronic Injury and Repair 75
Cancer and Aging 76
Met: The Missing Link? 78
Telomerase in Cancer and Stem Cells 79
Aneuploidy 80
Conclusion 81
References 81
Chapter 7: Cancer Stem Cells 83
Précis 83
Introduction 83
Matter and Energy 84
Invention of the Telephone 84
Pioneers of Cancer Stem Cell Research 85
Cancer Stem Cells 86
Origin of Cancer Stem Cells 86
The Making of a Rogue Cell 87
Snags in the Stem-Cell Theory 88
Spontaneous Remissions 89
Succisa Virescit 90
Putative Progenitor Stem Cells 91
The CML Model 91
Stem Cell vs. Progenitor Cell 92
Stem-Cell Theory of Cancer 95
Conclusion 95
References 96
Chapter 8: Cancer Niche 98
Introduction 98
The Dynamic Niche 99
The Embryonic Niche 99
Yin and Yang 100
Niche Matters 100
Donor-Cell Leukemia 101
Stromal Factors 102
Epithelial–Stromal Interactions 102
Hypoxia 103
Niche as an Investigative Medium 104
Niche as a Therapeutic Medium 104
Conclusion 105
References 106
Chapter 9: Ontogeny and Oncology 107
Précis 107
Introduction 107
The Nature of the Beast 108
The Power of Reiteration 108
Reactivation of Embryonic Genes 109
Resurgence vs. Reprogramming 110
Asymmetric Division 111
Polycomb Silencers 112
Epithelial-to-Mesenchymal Transition 113
Compartmentalization of Cancer 113
Clinical Implications 114
Conclusion 115
References 115
Chapter 10: Diagnosis and Prognosis 117
Introduction 117
Cancer 101 118
Personalized Cancer 119
Lethal vs. Indolent Ca.ncers 119
Stem-Cell Hierarchy 120
Selection vs. Evolution 121
Disease Selection by Therapy 122
Diagnosis and Prognosis 122
Methods and Norms 124
Rosetta Stone or Tower of Babel? 125
A Modest Proposal 126
Conclusion 126
References 127
Chapter 11: Cancer Targets 128
Précis 128
Introduction 129
Target du Jour 129
Paradigm Shift 129
Stem-Cell Theory 130
Death by a Thousand “Hits” 130
The Problem with the Gene Theory 131
Necessity or Redundancy? 132
Credentialing Cancer Targets 132
The Making of Human Cancer Cells 133
Field Defect 134
Cancer Targets in Nonmalignant Cells 134
Benign Prostatic Hypertrophy and Prostate Cancer 135
Endometriosis and Ovarian Cancer 136
Et Tu, Stromatogenesis? 137
Targeted Therapy 137
Clinical Implications 138
Conclusion 139
References 139
Chapter 12: Heterogeneity of Cancer 142
Précis 142
Introduction 142
Apples and Oranges 143
The Good, the Bad, and the Ugly 143
Stem-Cell Theory 143
Origin of Heterogeneity 144
HOX Genes 144
Stem Cells and Heterogeneity 145
Pluripotency 146
Genetic Instability 146
Clinical and Biologic Implications 147
Conclusion 148
References 149
Chapter 13: Metastasis 150
Précis 150
Introduction 150
Cell Migration and Tissue Repair 151
A Perfect Storm 151
The Metastatic Journey 152
A Modern “Seed-and-Soil” Theory 152
Stem Cells and Metastasis 153
Final Fury 154
Heterogeneity of Metastasis 154
Host–Cell Interactions 155
Stem-Cell Niche vs. Onco-Niche 155
Clinical and Biologic Implications 157
Conclusion 157
References 158
Chapter 14: Cancer Immunity 160
Précis 160
Introduction 160
Immune Surveillance 161
Immunotolerance 162
Human Leukocyte Antigen Expression 162
HLA-G and Immunotolerance 163
The Meaning of b2M 164
Immune Activation 165
Minimal Residual Disease 165
Cancer Vaccines 166
Melanoma 166
Renal-Cell Carcinoma 167
Cervical Carcinoma 167
Prostate Carcinoma 167
Autoimmunity 168
Conclusion 170
References 170
Chapter 15: Drug Resistance 173
Introduction 173
The Return of Cancer 174
Worst Enemies 174
ABC Transporters 175
DNA Repair 176
Apoptosis 176
“Teratomatous” Tumors 177
The Enigma of Somatic Cells 178
The Goldie–Coldman Principle 178
The Gompertzian Model 179
Clinical Pitfalls 180
Clinical Gems 182
An Exercise in Futility 183
An Uphill Battle 184
Conclusion 184
References 185
Chapter 16: Paradigm Shifts 188
Introduction 188
Dedifferentiation 189
Genetic Mutations 190
Multistep Carcinogenesis 191
The Story of Adenoma 192
It’s the Stem Cell! 193
Metastasis 194
Cancer Niche 195
Conclusion 196
References 196
Chapter 17: Experimental Proof 198
Précis 198
Introduction 198
The Culture of Cancer Research 199
Fundamental Flaws 200
Experimental Proof Already Extant? 200
Mesenchymal Origin 201
Transplantation Studies 201
Heterogeneity Studies 202
Metastasis Studies 203
Experimental Proof Still to Be Found! 203
Circulating Tumor Cells 204
Hox Genes 205
The Study of Stem Cells Helps the Study of Cancer 205
The Study of Cancer Helps the Study of Stem Cells 206
The Ultimate Experiment 206
A Modest Proposal 207
Conclusion 208
References 209
Chapter 18: Clinical Implications 211
Introduction 211
Response vs. Survival 212
Clinical Trials 213
The Problem with Randomization 214
Clinical Perspectives 215
Cancer Screening 215
Cancer Targets 216
Diagnosis and Prognosis 216
Therapeutic Implications 217
Chemoprevention 217
Surgery 218
Vaccine Therapy 219
Stem-Cell Therapy 220
Future Research Directions 220
Cancer Stem Cells 221
Stem-Cell Research 221
Cancer Epigenetics 222
Angiogenesis 223
Conclusion 223
References 224
Chapter 19: Curing Cancer 225
Précis 225
Introduction 225
Conquest vs. Cure 226
Personalized Therapy 227
Chemoprevention 228
Differentiation Therapy 229
Surgery: To Operate or Not to Operate? 230
Maintenance Therapy 231
Targeted Therapy 232
Basic Rules of Science 233
Conclusion 234
References 234
Chapter 20: Epilogue 236
Introduction 236
Cancer’s Boogeyman 237
Legend of the Fall 238
The Curse of Job 238
The Big Fix 239
A Tale of Two Cells 239
Old Dogma and New Doctrine 240
Trade-offs 241
Quo Vadimus? 241
Final Thoughts 242
Glossary 244