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aboriginal populations, 85–88, 203
abscopal effect, 305–7
acute myelogenous leukemia (AML), 142
adaptive therapy, 308–9
adenomas and polyps, colonic, 104, 174, 187, 199, 269–70, 285, 292
adhesion molecules, 139, 236, 240, 256
adoptive T cell transfer, 303–4
aerobic energy production, 36–37, 134, 135
aerobic glycolysis. See Warburg effect; Warburg effect and Warburg revival
age and cancer risk, 74, 75, 85, 298, 299–300
Allison, James, 301, 302–3
American Cancer Society, 11, 71, 263, 269, 271
American Diabetes Association, 205
American Heart Association, 189
American Society for the Control of Cancer, 7
amino acids, 218, 233, 234–35
aminopterin, 193
AML (acute myelogenous leukemia), 142
AMP (adenosine monophosphate), 220
AMPK (AMP-activated protein kinase), 220–22, 225
anaerobic energy production, 36, 134, 135
anaplasia, 142
angiogenesis, 34, 38, 236, 238
antibiotics, 63–64, 143, 158–60
antibodies, 25, 78–79
antifungals, 217, 219, 237
antioxidants and antioxidant defenses, 51, 135, 191, 195
antiviral drugs, 60, 101, 267
apoptosis
acidic environments and, 237
as anticancer defense, 33, 176, 223–24, 225–26, 252
cancer cell resistance to, 31–34, 38, 223
DNA/cell damage and, 31–32, 138, 158, 223, 225, 298
extrinsic and intrinsic pathways, 223–26
growth factor prevention of, 223–24
insulin/IGF-1 and, 222–24
mitochondria and, 134
radiation-induced, 51
resource scarcity and, 145
vitamin D and, 194
artificial radioactivity, 49
artificial selection, 151–52
asbestos, 44–47, 105, 122
asexual reproduction, 146
Aspirin/Folate Prevention of Large Bowel Polyps trial, 192
atavism, 148, 164–68, 169, 179, 254
atomic bomb, 50–51, 174
ATP (adenosine triphosphate), 36, 134, 135, 140, 220, 229–33
Australia antigen, 59
Australian Polyp Prevention Project, 187
autoimmune diseases, 21, 176, 301
autonomy, 142–43
autophagy, 220, 224–25, 290
axicabtagene ciloleucel, 304
Bacillus Calmette–Guérin (BCG) vaccine, 300–301
bacteria. See also viruses and bacteria, cancers caused by
antibiotics and, 143, 158–60, 237, 283
antifungal production and, 217, 219, 237
chronic sublethal damage and, 298
competition for resources, 145
growth and, 137, 161
H. pylori and stomach cancer, 62–64, 65, 90, 122, 174
movement by, 138, 239
photosynthetic, 140
protozoans compared to, 135
spontaneous regression and, 294–97
Bailar, John, III, 7–9
bariatric surgery, 286–87
Barrett’s esophagus, 175
basal cell carcinoma, 17
basal metabolic rate (BMR), 289
Baselga, José, 109–10
basement membranes, 236, 237, 240, 255
Bateson, William, 69
bcr/abl kinase, 76
Becquerel, Henri, 21–22
benign cancers, 12, 17, 34–35, 239
benzopyrene, 43–44
Berenblum, Isaac, 23
beta-carotene, 191
bevacizumab, 114
Bishop, Mike, 70
Blackburn, Elizabeth, 33
bladder cancer, 266, 300–301
blastema theory, 18–19
blood cancers, 28, 80. See also leukemia; lymphoma; myeloma
bloodstream, cancer cells in. See circulating tumor cells (CTCs)
blood transfusions, 59–60
blood vessel growth, 34, 38, 236, 238
Blumberg, Barry, 59
body mass index (BMI), 196–98
bone cancer, 15
bone marrow, 23, 49, 142
bottlenecking, 249
Boveri, Theodor, 69–70
branched-chain evolution, 154–59, 254, 276
BRCA1 gene, 30–31, 71, 83, 84, 161, 171
BRCA2 gene, 30–31, 71, 84
breast cancer. See also BRCA1 gene; BRCA2 gene
cancer deaths vs. overall deaths, 273, 274
cell growth and reproduction, 142
diet and, 190, 192, 195, 290
environmental vs. heritable factors, 85, 87, 88–90, 122
height and, 209
HER2/neu and drug for, 78–81, 157
insulin/IGF-1 and, 206, 207, 214, 216
late-stage diagnosis, 273, 274–76
lead time bias and, 273–74
metastatic, survival rates for, 267–68
metformin and reduced risk of, 291
origin of cells, 17, 27–28
overdiagnosis of, 276
preventative mastectomy and, 83
radiation and secondary cancers, 176
rapamycin and, 219
screening and, 267, 268, 271, 272–78
self-seeding and, 246
as a solid organ and tissue cancer, 28
speciation and, 172
surgery for, 19–20
surrogate outcomes and drugs for, 114
type 2 diabetes and, 205
weight and, 198, 199, 201, 267
Burkitt, Denis Parsons, 53–55, 186–87, 203, 215
Burkitt’s lymphoma, 53–56
Burnet, Frank, 297
Busch, Wilhelm, 295
calorie counting, 4–5
calorie restriction, 200–201, 220, 287
cancer, as term, 27
cancer, origins of. See origins of life and origins of cancer
cancer cachexia, 145, 198, 288–90
Cancer Genome Atlas (TCGA), 10, 92–93, 95, 100, 124, 153
cancerous transformation, 169–81. See also transformation
cancer’s mysteries, explaining, 178–79
carcinogenesis, 173–77
mutations at intersection of unicellularity and multicellularity, 169–72
new understanding of cancer, 180–81
speciation, 172–73
Cancer Paradigm 1.0. See excessive growth, cancer as
Cancer Paradigm 2.0. See genetic disease, cancer as
Cancer Paradigm 3.0. See evolutionary model of cancer
cancer prevention and screening, 263–84
breast cancer, 272–78
cervical cancer, 268–69
colorectal cancer, 269–71
decline in cancer deaths and, 263–65
evolutionary model of cancer and, 282–83
overdiagnosis and, 276, 279–80, 282, 283
prevention, 265–67
screening, 267–68
Cancer Prevention Study II, 197, 204
“Cancer Undefeated” (Bailar), 9
Cantley, Lewis, 211, 213, 215, 234
carbohydrate restriction, 200–201, 287–88, 290
carbohydrates, dietary, 87, 126, 206, 215, 220, 221
carbon, 233
carcinogenesis, 71, 74–75, 173–77, 259. See also cancerous transformation
carcinogens, 41–51. See also group 1 carcinogens; viruses and bacteria, cancers caused by
apoptosis and, 223
asbestos, 44–47, 105
chemotherapy drugs, 47, 176
chronic sublethal damage and, 173–76
epigenetics and, 124
genetic mutations and, 72–75, 81
groups of, 46–47
radiation, 47–51
soot, 42–44
tobacco, 41–42
carcinoma (cancer) of unknown primary, 240, 244–45
Carswell, Robert, 19
catechins, 291
CD28 (costimulatory receptor), 302
CDC (Centers for Disease Control and Prevention), 4, 5, 198
cell death, controlled. See apoptosis
cell divisions, limited. See Hayflick limit
cells
chronic sublethal damage to, 173–76, 180, 253–54, 298
cooperation between, 136, 148
early in evolution, 133–35
movement of, 138–39, 140–41, 239, 255, 256
specialization of, 135–36, 141–42
cellular energetics, 36–37, 220, 221, 229. See also glucose metabolism; glycolysis; oxidative phosphorylation (OxPhos); Warburg effect and Warburg revival
Celsus, 16
cervical cancer
cigarette smoking and, 266
human papillomavirus (HPV) and, 60–61, 122
precancerous lesions and, 174, 269, 276
radium treatment for, 22
screening and, 7, 117, 268–69, 271, 273
chemoprevention, 291–92
chemotherapy. See also drugs, cancer
cancer as excessive growth and, 293–94
carcinogenic drugs used for, 47, 176
fasting and, 290–91
folate and, 193
history of cancer and, 23–25
post-surgery, 245
rapamycin and, 219
resistance and, 159, 308–9
toxicity of, 274, 283, 304
tumoral evolution and, 155, 158, 159
children, 9, 24–25, 30, 53–56, 159
chimeric antigen receptor (CAR-T), 304
chimney sweeps, scrotal cancer in, 42–44
China, 56–57, 59, 89, 296–97
chlorambucil, 24, 176
chloroquine, 56
cholesterol, 189
choriocarcinoma, 24
chromosomes, 69
chronicity, 173–75
chronic myelogenous leukemia (CML), 76–78, 80, 95, 109, 122, 157. See also imatinib
Ciba-Geigy, 76
circulating tumor cells (CTCs), 241, 244, 246–48, 256
cirrhosis, 101, 267
Clostridium, 295
CML. See chronic myelogenous leukemia (CML)
Cochrane Library, 272
Coley, William, and Coley’s toxins, 294–97, 305
colon/colorectal cancer
cell growth and reproduction, 142
cigarette smoking and, 266
decline in deaths from, 269, 271
diet and, 186–88, 190, 192, 195
DNA methylation and, 124
environmental vs. heritable factors in causation of, 85, 87
gastric bypass surgery and, 287
genetic mutations and, 94–95, 96, 108
increase in younger patients, 271
insulin/IGF-1 and, 206–7, 214, 216, 287–88
metastatic, survival rates for, 267–68
precancerous lesions and, 104, 174, 187, 199, 269–70, 285, 292
screening and, 267, 268, 269–71, 285
self-seeding and, 246
as a solid organ and tissue cancer, 28
treatment cost, 118
type 2 diabetes and, 205
weight and, 198, 199–200, 267, 271
colonoscopy, 270–71, 285
competition for resources, 145
convergent evolution, 162–64, 168
COSMIC (Catalogue of Somatic Mutations in Cancer), 170
Cowden syndrome, 214
C-peptide test, 206–7
crizotinib, 109
CTCs (circulating tumor cells), 241, 244, 246–48, 256
CTLA-4 (cytotoxic T-lymphocyte-associated protein #4), 302–3, 307
CT scans, 20
Curie, Marie and Pierre, 21–22, 47–49
cyclophosphamide, 24, 47, 176
cyclosporin, 176
Darwin, Charles, 27–29, 151, 155, 180. See also natural selection dasatinib, 111, 116
Davies, Paul, 125, 129–30, 133, 148
dedifferentiation, 168, 171
denominator problem, 99–101
DeVita, Vincent, Jr., 9
diabetes, type 2. See type 2 diabetes
dietary determinants of cancer, 285–92. See also cancer cachexia; nutrition and cancer; obesity; type 2 diabetes; weight loss
dietary guidelines, 126–27, 128
DNA (deoxyribonucleic acid). See also genes; mutations
antibodies and specific sequences of, 79
damage to, 71–73, 158, 173–74, 306–7
epigenetics and, 123–24
inherited traits and, 69
mitochondrial, 134
DNA methylation, 123, 124
DNA-repair mechanisms, 146, 176–77, 252, 298
DNA surveillance, 176–77
Doll, Richard, 185
driver mutations, 96, 100–101, 108
drug resistance, 106, 158–59, 304, 308–9
drugs, cancer, 11–13, 25, 79, 106, 109–18, 258–59. See also chemotherapy; hormonal treatments; imatinib; trastuzumab
ductal carcinoma in situ (DCIS), 277–78
dwarfism, 215–16
EBV (Epstein-Barr virus), 55–56, 65, 87
Ecuador, 215–16
Edwin Smith Papyrus, 15
egfr gene, 70
Egyptians, ancient, 15, 19, 44, 85
Ehrlich, Paul, 297
Einstein, Albert, 127, 128
Eisenhower, Dwight D., 188
endometrial cancer, 198, 199, 200, 205, 216
environment and cancer risk
aboriginal populations and, 85–88, 203
developing new paradigms, 125–31
epigenetics, 123–25
evolutionary paradigm and, 259–60
genetics vs., 121–22
migrant studies and, 88–90
somatic mutation theory (SMT) and, 87–88, 106–7, 122, 124
traditional vs. Western lifestyles, 85–88, 186–88, 203–4, 215
twin studies and, 83–85
epigenetics, 123–25, 177
Epstein-Barr virus (EBV), 55–56, 65, 87
erysipelas, 295–96
esophageal cancer, 100–101, 175, 198, 199, 266, 267–68
estrogen, 27–28
eukaryotes, 134, 135, 140, 251
European Randomized Study of Screening for Prostate Cancer (ERSPC), 279
everolimus, 114
evolution, branched-chain, 154–59, 254, 276
evolution, convergent, 162–64, 168
evolutionary model of cancer (Cancer Paradigm 3.0), 251–60. See also metastasis; progression; transformation
Cancer Paradigms 1.0 and 2.0 and, 257–60
evolution from unicellular to multicellular organisms, 148–49, 251–53
immunotherapy and, 294, 310
war on cancer and, 180
evolution of cancer cells, 245–49. See also tumoral evolution
excessive growth, cancer as (Cancer Paradigm 1.0), 1–65
carcinogens and, 41–51
hallmarks of cancer, 28–39
history of cancer, 15–25
insulin and, 213–14
mutations and, 69–70, 73, 81
obesity and, 210–11
viruses and bacteria and, 53–64
war on cancer and, 7–13, 180, 258, 293–94
extracellular matrix, 144, 237, 238
extravasation, 240, 241–42
eye cancers, 30, 71
familial cancers, 71, 72
Farber, Sidney, 24, 193
fasting, 289, 290–91
fat, dietary, 87, 126, 128, 187, 188–90, 221, 288
fatty acids, 233, 235. See also omega-3
fatty acids fatty liver disease, 211, 267
FDA (Food and Drug Administration)
drug approvals and, 11–12, 111, 114, 115, 300, 303, 304, 310
prostate cancer screening and, 11–12, 111, 114, 115, 278–79
fecal occult blood testing (FOBT), 270–71
Fehleisen, Friedrich, 295
fermentation. See glycolysis
Feynman, Richard, 127–28
fiber, dietary, 186–88
Fleming, Alexander, 6, 143, 237
folic acid (Vitamin B9), 24, 192–93
Food Guide Pyramid (1992), 126
founder effect, 215
fractionated radiotherapy, 22
Frei, Emil, 24–25
Freirich, Emil, 24–25
Galapagos finches, 151, 152, 155
Galen, 16
gallbladder cancer, 199, 200
Gardner, Leroy, 45–46
gastric bypass surgery. See bariatric surgery
gastritis, 63–64
gastroesophageal reflux disease (GERD), 175
Gatenby, Robert, 308–9
gene expression, 123–24, 171
Genentech, 78–80
General Practice Research Database (U.K.), 207
genes, 29–30, 69–70. See also gene expression; mutations; oncogenes; tumor suppressor genes; specific gene names
genetic disease, cancer as (Cancer Paradigm 2.0), 67–118. See also environment and cancer risk; somatic mutation theory (SMT)
denominator problem, 99–101
environment and, 83–90, 106–7
genetically targeted drugs and, 106, 109–12, 258–59
preposterous reductionism and, 105–8
proximate vs. root causes, 101–5
raising drug prices and, 116–18
somatic mutation theory (SMT) and, 69–81
surrogate outcomes and, 112–15
war on cancer and, 9–10, 91–97, 118, 180, 258–59, 294
genetic revolution, 69–75, 233
genetics, as term and scientific field, 69
genetic variation and diversity, 146–47, 152, 153, 245–49
genital warts, 60–61
genome driven oncology, 109–11
genomic instability, 35, 146–47
genomic stability, 146, 158
GERD (gastroesophageal reflux disease), 175
Germany, 58–59
Gleevec. See imatinib
glucose
cancer’s requirement for, 37, 231, 232, 236, 238, 255, 289
dietary carbohydrates and, 288, 290
insulin and entry into cells, 143
metformin and, 291
mTOR pathway and, 218
glucose metabolism, 36–37, 135, 140–41, 206, 208, 213–14, 229–34. See also glycolysis; oxidative phosphorylation (OxPhos); Warburg effect
GLUT1 glucose transporters, 37
GLUT4 glucose transporters, 213, 214
glutamine, 234–35, 290
glycolysis. See also Warburg effect
cancer cells and, 37, 215, 231
hypoxia-inducible factor (HIF) and, 236
OxPhos compared to, 36–37, 229–30
p53 gene and, 234
in present-day mammalian cells, 135
unicellular vs. multicellular organisms and, 140–41
Great Fire of London (1666), 42
Greeks, ancient, 15, 16, 17–18, 19–20, 44
green tea, 220, 291–92
Greider, Carol, 33
group 1 carcinogens, 47, 50, 64, 176
growth, cellular. See also excessive growth, cancer as
AMPK and, 220, 255
exponential, 144
insulin and, 211–12, 255
metabolism and, 213, 214, 226, 234
mTOR pathway and, 218–19, 255
unicellular vs. multicellular organisms, 137, 140–41
wound healing vs. cancer, 174
growth factors, 209–16
apoptosis prevention by, 223–24
cancer progression and, 225–26, 249
excessive growth conditions, 209–11
insulin, 211–15
insulin-like growth factor (IGF-1), 215–16
lactic acid and, 238, 255
nutrient sensors as, 226
growth hormone (GH), 215–16
growth suppressors, evasion of, 30–31, 38
Grubbe, Emil, 21
Guevara-Aguirre, Jaime, 216
Haber, Fritz, 23
Hahn, W. C., 105–6
hallmarks of cancer, 28–39
angiogenesis, inducing, 34, 38, 236, 238
cell death, resisting, 31–32, 38, 223
cellular energetics, deregulating, 36–37, 38
defining cancer and, 38–39
emerging, 35
enabling characteristics, 35
growth suppressors, evasion of, 30–31, 38
hallmarks of unicellularity and, 140–41
immune destruction, evading, 37–38
invasion and metastasis, activating, 34–35, 38, 236, 238
proliferative signaling, sustaining, 29–30, 38
replicative immortality, enabling, 32–34, 38
Warburg effect, 231, 236
“The Hallmarks of Cancer” (Hanahan and Weinberg), 28–29, 35
Halsted, William, 20
Hanahan, Doug, 28–29, 35, 236
Hanway, Jonas, 43
Hausen, Harald zur, 60–61
HAV (hepatitis A virus), 58, 174
Hawaii, 90
Hayflick limit, 32–33, 176–77, 252
HBV (hepatitis B virus), 58–59, 60, 65, 174, 266–67
HCV (hepatitis C virus), 59–60, 65, 101, 174, 266–67
Health Professionals Follow-up Study, 287
heart disease
cancer compared to, 10–11, 147–48, 263
diet and lifestyle and, 186, 188–90, 191, 192, 194–95, 196, 197
excessive growth and, 211
tobacco smoke and, 265
heart drugs and surrogate outcome, 112
height, 209, 210–11, 215–16
HeLa cells, 33
Helicobacter pylori, 62–64, 65, 90, 122, 174
hepatitis A virus (HAV), 58, 174
hepatitis B virus (HBV), 58–59, 60, 65, 174, 266–67
hepatitis C virus (HCV), 59–60, 65, 101, 174, 266–67
hepatoma, 16
HER2/neu gene, 78–80, 157
Herceptin. See trastuzumab
Herodotus, 15, 44
Hill, John, 41–42
Hippocrates, 16
history of cancer, 15–25
HIV (human immunodeficiency virus), 37, 65, 200, 298
Hodgkin’s disease (Hodgkin’s lymphoma), 25
Honjo, Tasuku, 303
HOPE2 randomized trial (2006), 192
hormonal treatments, 159, 257, 308
hormones, 29, 143, 146, 213, 215–16. See also insulin; insulin-like growth factor (IGF-1)
host destruction, 143–44
HPV (human papillomavirus), 60–61, 122, 268–69
human drug trials, 76–77
Human Genome Project, 10, 92
human immunodeficiency virus (HIV), 37, 65, 200, 298
human papillomavirus (HPV), 60–61, 122, 268–69
humoral theory of disease, 17–18
Hungerford, David, 76
hyperinsulinemia, 203–8
consumption of sugar and refined grains and, 215
dietary prevention of cancer and, 286–88
excessive growth and, 214–15
insulin and cancer, 206–8
in millennials, 200
type 2 diabetes, obesity, and cancer, 203–6, 215, 226
hypoxia-inducible factor (HIF), 235–36, 255
hypoxic zone, 235
IGF-1 (insulin-like growth factor), 215–16, 223–24, 226, 287–88, 290
imatinib, 76–78, 80–81, 95, 106, 109–11, 116–18, 122, 159
Imhotep, 15, 295
immortality, replicative, 32–34, 38, 138, 140–41, 174
immune editing, 297–300
immune surveillance, 176–77, 246, 252, 297
immune system, 37–38, 237–38, 241–42, 255, 294–97, 298, 301
immunosuppressive drugs, 37, 217–18, 219, 237
immunotherapy, 293–310
abscopal effect, 305–7
adaptive therapy, 308–9
cancer paradigms and, 293–94
Coley’s toxins, 294–97
early years of immunotherapy, 300–301
evolutionary model of cancer and, 294, 310
immune editing, 297–300
modern immunotherapy, 301–5
inactivity and cancer risk, 186
India, 190
Indigenous peoples, 85–88, 203
infections. See also viruses and bacteria, cancers caused by
cancer’s resemblance to, 147–48, 158–60, 172–73, 239
Coley’s toxins and, 294–97
infectious mononucleosis, 55
inflammation
chronic, and carcinogenesis, 176
fatty liver disease and, 267
green tea and reduction of, 291–92
H. pylori and, 63, 64
humoral theory of disease and, 17
intermittent fasting and, 290
lactic acid and, 237–38, 255
of the liver, 58–60
necrosis and, 31
surgery and, 287
tumor-promoting, 35
inflammatory breast cancer, 15
inflammatory cytokines, 289
inflammatory oncotaxis, 176
innate immune system, 241, 297
insulin. See also hyperinsulinemia
anti-apoptosis and, 223–24
cancer and, 206–8, 215, 226
dietary carbohydrates and, 287–88
evolutionary model of cancer and, 249, 255
fasting and, 290
function of, 143, 206
as growth factor, 211–15, 234
IGF-1 and, 215–16
link between obesity and type 2 diabetes and, 201, 205
mTOR pathway and, 218–19
as nutrient sensor, 206, 208, 212, 213, 214–16, 221–22, 225
treatment with, 6, 207–8
insulin-like growth factor (IGF-1), 215–16, 223–24, 226, 287–88, 290
insulin receptor, 213, 214
insulin resistance, 205, 291–92
interleukin-2 (IL-2) treatment, 301
International Agency for Research on Cancer (IARC), 46–47, 64, 176, 198
International Cancer Genome Consortium, 93
intratumoral heterogeneity (ITH), 153, 155, 159, 248, 254
intravasation, 240–41
Inuit people, 56, 87–88, 188, 189–90, 203–4
invasive species, cancer as, 172–73, 180, 191, 252, 254, 256, 294, 308
ipilimumab, 302–3, 305
Japan, 62, 88–89, 90, 122, 266, 267, 292
jaundice, 18, 58–59
Jolie, Angelina, 83
Joliot-Curie, Irène and Frédéric, 49
karkinos, 16
ketogenic diets, 288
ketone bodies, 289
Keynes, John Maynard, 5
Keys, Ancel, 189
Khan, Arshid Ali, 164
kidney cancer, 71, 198–200, 206, 235, 266, 303
Korea, 64
Krebs, Hans, 288
Lacks, Henrietta, 33
lactic acid, 36, 229–31, 235–38, 255
Laron dwarves, 215–16
late-stage diagnosis, 273, 274–76
lead time bias, 273–74
Leakey, Louis, 15
Leonidas of Alexandria, 19
leukemia. See also acute myelogenous leukemia; chronic myelogenous leukemia
as a blood cancer, 28
in children, chemotherapy for, 24–25, 159
cigarette smoking and, 266
folate supplementation and, 193
genetic mutations and, 96
modern immunotherapy for, 304
radiation exposure and, 49
viruses causing, 55
Li, Min Chiu, 24
life, origins of. See origins of life and origins of cancer
Life Span Study (LSS), 50
lifestyles, traditional vs. Western, 85–88, 186–88, 203–4, 215
Lineweaver, Charley, 125
lipoma, 12, 17, 239
liver cancer, 59–60, 197–99, 205, 266–67, 296–97
liver disease and failure, 58–60, 101, 211, 267
Lotka-Volterra equations, 308
lumper-splitter problem, 27
lung cancer
asbestos and, 45–46
cigarette smoking and, 122, 126, 265–66
crizotinib treatment for, 109
decline in deaths from, 263–64, 265
evolutionary model and metastasis, 251–57
genetic mutations and, 96, 103
insulin and, 206
modern immunotherapy for, 303
rapamycin and, 219
as a solid organ and tissue cancer, 28
traditional vs. Western lifestyle and, 87
vitamin E supplementation and, 195
weight not associated with, 198, 200
lung disease, 45, 126, 188–89, 265. See also lung cancer; mesothelioma
lymphoma, 15, 23–24, 25, 28, 235, 304. See also Burkitt’s lymphoma; MALT lymphoma
lymph theory, 18
malaria, 56
malignant cancers, 12, 17, 240
MALT lymphoma (mucosa-associated lymphoid tissue), 64
mammography, 271, 272–78
Marshall, Barry, 62–64
mastectomy, radical. See radical mastectomy
mathematical oncology, 308–9
maximally tolerated dosage (MTD), 309
Maynard, D. G., 204
Mayo Clinic, 41
melanoma
abscopal effect and, 305–6
defined, 16
genetic mutations and, 96
interleukin-2 (IL-2) treatment for, 301
modern immunotherapy for, 303, 304
organ transplant and, 298–99
self-seeding and, 246
sunlight exposure and, 194
melphalan, 176
Memorial Sloan Kettering Cancer Center, 24, 109–10
Mendel, Gregor, 69
meningioma, 199
mesothelioma, 45, 46, 105, 122
metabolism and growth, 213, 214, 226, 234. See also glucose metabolism; Warburg effect
metaplasia, 175
metastasis, 227–49
abscopal effect and, 305
activating invasion and, 34–35, 38, 236
branched-chain evolution and, 156
cancer treatments and, 12–13, 20, 22
CTCs and micrometastasis, 243–45, 257
defined, 239
evolutionary model and, 249, 256–57
genetic mutations and, 97
hypoxic acidic environment and, 241, 246, 248
IGF-1 and, 216
immunotherapy and, 304–5
invasion by single-cell organisms compared to, 145
latent, 245, 299
mortality and, 17, 34, 112–13
processes of invasion and, 240–43
tumoral evolution and self-seeding, 245–49, 256
Warburg revival, 229–38
metformin, 207, 220, 290, 292
micrometastases, 35, 243–45, 246, 248, 257, 304–5
migrant studies, 88–90
Miller, Stanley, 133
Million Women Study (U.K.), 209, 210
Minnesota Colon Cancer Control Study, 271
mitochondria, 36, 134, 135, 140, 220, 224–26, 232, 236
mitophagy, 224, 225, 290
Molecular Analysis for Therapy Choice (NCI-MATCH) trial, 110–11
mortality rates, cancer, in the United States, 7–9, 10–11, 13, 263–64
mosquitos and Burkitt’s lymphoma, 54, 55, 56
movement of cells, 138–39, 140–41, 239, 255, 256
mTOR and mTOR pathway, 214–15, 217–22, 225, 249, 255, 288, 290
Müller, Johannes, 18–19
multicellular organisms
anticancer defenses in, 176–77, 252–53
autonomy and, 143
cancer subroutine in, 178, 254
cell boundaries in, 145
controlled cell death in (See apoptosis)
cooperation and, 148–49, 170, 251–53
extracellular environment and, 144
genes developed at onset of existence of, 169–71, 252
genomic stability in, 146–47
growth control in, 137, 144
insulin as nutrient sensor in, 212
resource scarcity and, 145
single-cell organisms compared to, 135–41, 251–52
specialization and, 142
multiple myeloma, 117, 199, 200
mustard gas, 23–24
mutations. See also somatic mutation theory (SMT)
acquired, 73, 74
cancer development and, 39, 41, 70–75
complexity of, in cancer, 94–97
convergent evolution and, 162–64
excessive growth and, 69–70, 73
genomic instability and, 35, 146–47
inherited, 71, 72
ionizing radiation and, 49–50
multiple, accumulation of, 71–74
in oncogenes, 70, 72
randomness, lack of, in causing cancer, 103–5, 242–43, 254
in tumor suppressor genes, 30–31, 70, 71, 72
myc gene, 70, 174, 234
Mycobacterium bovis, 300
Mycobacterium tuberculosis, 300
myeloma, 28. See also multiple myeloma
myopia, 209–11
Nagahara, Larry, 125
nasopharyngeal cancer (NPC), 56–57, 87
National Cancer Act, 7
National Cancer Advisory Board, 58
National Cancer Institute
budget for, 11, 91
chemotherapy for choriocarcinoma and, 24
metastasis definition of, 239
Molecular Analysis for Therapy Choice trial, 110–11
Office of Cancer Investigations merged into, 23
research focus change, 125, 129
Special Virus Cancer Program (SVCP), 57–58
National Health and Nutrition Examination Survey (NHANES), 194, 207
National Institutes of Health (NIH), 194–95, 219, 291
National Polyp Study, 271
Native Americans and Canadians, 86–88
natural killer (NK) cells, 37, 172, 241, 252–53
natural selection, 151, 152, 153, 162, 246–48, 254. See also selective/selection pressure
necrosis, 31–32, 223, 306–7
neural tube birth defects, 192
neuroblastoma, 235
NIH (National Institutes of Health), 194–95, 219, 291
nilotinib, 111
Nixon, Richard, 7, 22, 57, 91
N-nitrosamine, 57
Nógrády, Georges, 217
non-Hodgkin’s lymphoma, 23
Norwegian Vitamin (NORVIT) trial, 192
NOTCH1 gene, 100–101
Nowell, Peter, 76
Nurses’ Health Study, 187, 201, 206–7, 287
nutrient sensors, 217–26. See also insulin; insulin-like growth factor (IGF-1)
AMPK, 220–22
growth and, 213, 222, 226, 234, 255
insulin/IGF-1, 206, 208, 212, 213, 214–16, 221–22, 287
mTOR pathway, 214–15, 217–22
nutrition and cancer, 185–201. See also dietary determinants of cancer; dietary guidelines; obesity
diet and cancer risk, 185–86, 195
dietary fat, 188–90, 196
dietary fiber, 186–88, 195
obesity, 186, 189–90, 196–201
vitamins, 190–95, 196
Obama, Barack, 11, 110
obesity
cancer risk and, 186, 196, 197–201, 210–11, 215, 263, 267, 286
dietary prevention of cancer and, 286
epidemic of, 4–5
excessive growth and, 210–11, 214
GERD and Barrett’s esophagus risk and, 175
glucose levels and, 233
green tea and, 291–92
insulin/IGF-1 and, 224, 287
intermittent fasting and, 290
traditional vs. Western lifestyles and, 186, 188, 203–4
type 2 diabetes and, 197, 201, 203, 205
Office of Cancer Investigations, 23
Ohsumi, Yoshinori, 224
Ojibwa people, 86–87
omega-3 fatty acids, 194–95
oncogenes. See also specific oncogene names
discovery and definition of, 30, 70, 129
growth control and, 137
junction of unicellular and multicellular life and, 170–71, 252
metabolic pathways and, 234
mutations in, 70, 72, 171, 174
overexpression of, 78–79
oncos, 16
“On the Origin of Cancer” (Warburg), 232
On the Origin of Species (Darwin), 151
organelles, 134, 135, 138, 225
organ transplants, 298–99
The Origin of Malignant Tumours (Boveri), 69–70
origins of life and origins of cancer, 133–49
autonomy, 142–43
cancer’s resemblance to infection and, 147–48
competition for resources, 145
early cells, 133–35
exponential growth, 144
genomic instability, 146–47
host destruction, 143–44
invasion into novel environments, 144–45
multicellularity, jump to, 135–41, 149
reversion toward unicellularity, 148–49
specialization, 141–42
osteoporosis, 186
ovarian cancer, 83, 161, 171, 198, 199
oxidative phosphorylation (OxPhos)
glycolysis compared to, 36–37, 229–30
hypoxia-inducible factor (HIF) and, 236
mitochondria and, 134
oxygen availability and, 135, 140
p53 gene and, 234
Warburg effect and, 230–33, 238
oxygen, 36, 134–35, 140, 218, 229–32, 235–36
p53 gene, 31, 70, 158, 171, 234
paclitaxel, 117
Paget, Stephen, 121
PanCancer Atlas, 93
pancreatic cancer
cigarette smoking and, 266
genetic mutations and, 96
glutamine and, 235
insulin and, 206
metastatic, survival rates for, 267–68
overweight and obesity and, 199, 200, 267
screening and, 268
type 2 diabetes and, 205
Papanicolaou, George N., 269
papillomavirus, 55
Pap smear, 7, 268–69, 273
passenger mutations, 96, 108
Pauling, Linus, 193
penicillin, 6, 143, 237
peptic ulcer disease, 63–64
pesticides, 56, 308–9
PET (positron emission tomography), 37, 231, 305
Peto, Richard, 185
Philadelphia chromosome, 76–78, 95, 122
phosphoinositide 3-kinase (PI3K) pathway, 211–12, 213–14, 216, 223–24, 226, 290
photosynthesis, 134–35, 140
phylostrata, 169–70
Physical Sciences–Oncology Centers, 125
physics and cancer research, 125, 127–28
PI3K (phosphoinositide 3-kinase) pathway, 211–12, 213–14, 216, 223–24, 226, 290
pitchblende, 47–48
pleural mesothelioma, 45. See also mesothelioma
polonium, 48
polyps, colonic. See adenomas and polyps, colonic
positron emission tomography (PET), 37, 231, 305
Pott, Percivall, 42, 43
precancerous lesions, 269–70, 276, 292. See also adenomas and polyps, colonic
Precision Medicine Initiative Cohort Program, 110
preposterous reductionism, 105–8, 131
Procrustean bed, 94–97
progesterone, 27–28
programmed cell death. See apoptosis
programmed cell death protein 1 (PD-1), 303, 307
progression, 183–226
evolutionary model and, 249, 255
growth factors, 209–16
hyperinsulinemia, 203–8
nutrient sensors, 217–26
nutrition and cancer, 183–201
progression-free survival (PFS), 112–15
prokaryotes, 134, 135, 251
proliferative signaling, sustaining, 29–30, 38
Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, 279, 280
prostate cancer
environmental vs. heritable factors in causation of, 88–89, 90
green tea and, 292
high incidence of, 285
insulin/IGF-1 and, 216
metastatic, survival rates for, 267–68
origin of cells, 17, 28
overdiagnsosis of, 279–80, 283
rapamycin and, 219
rate in United States, 279, 280
screening and, 267, 268, 278–81
as a solid organ and tissue cancer, 28
vitamin supplementation and, 192, 195
prostate-specific antigen (PSA), 28, 271, 278–81
Prostate Testing for Cancer and Treatment (PROTECT), 279
protein, dietary, 87, 206, 218, 220, 221, 225, 288
proto-oncogenes, 29–30
protozoans, 135, 148, 159, 180
proximate vs. root causes, 101–5
PSA (prostate-specific antigen), 28, 271, 278–81
PTEN gene, 174
PubMed.gov, 91
pustules, 17–18
quality-adjusted life year (QALY), 117–18
radiation
abscopal effect and, 305–7
as a carcinogen, 47–51
chronic sublethal damage and, 174, 175, 176, 298
genetic mutations and, 72–73
history of cancer and, 21–22
post-surgery, 245
resistance and, 159, 308
unicellular cells and, 176
radiation oncology, 21–22
radical mastectomy, 20
radium and radium treatment, 22, 48
Radium Girls, 48–49
random accumulation hypothesis
evolutionary paradigm and, 148, 152, 160–61, 171, 177
metastasis and, 242–43, 245
somatic mutation theory and, 71–74, 94, 103–5, 152, 160–61
rapamycin, 217–18, 219, 237
Rb gene, 30
regorafenib, 118
replication, 133–34, 137, 138, 142
replicative immortality, enabling, 32–34, 38
reproduction, 133–34, 135, 137, 139, 142, 146
resistant strains of cancer, 308–9
respiration. See oxidative phosphorylation (OxPhos)
response rate (RR), 112–15
retinoblastoma, 30, 73–74
retinoblastoma tumor suppressor gene, 71
Revlimid, 117
ribonucleic acids (RNA), 133
Romans, ancient, 16, 44–45
Röntgen, William, 21
root vs. proximate causes, 101–5
Rous, Peyton, 54–55, 200
Rous sarcoma virus (RSV), 55, 70
salivary gland cancer, 87
San Francisco, California, 89
sarcoma, 16, 30, 48–49, 54–55, 296
Saskatchewan, Canada, 207
screening. See cancer prevention and screening
scrotal cancer, 42, 43–44
scurvy, 193
secondary cancers, 176
Sehgal, Suren, 217
selective/selection pressure
cancerous transformation and, 174, 175, 254
circulating tumor cells (CTCs) and, 246–48, 256
Darwin’s natural selection and, 152
treatment resistance and, 257, 308–9
tumoral evolution and, 157, 160–61
self-seeding and tumoral evolution, 245–49, 256
senescence, 33, 138
Serratia marcescens, 296
sexual reproduction, 146
sigmoidoscopy, 270
single-cell organisms. See unicellular organisms
skin cancer, 17, 28, 72. See also melanoma
Smithers, D. W., 259–60
smoking. See also lung cancer
cancer risk and, 41, 122, 186, 188–89, 265–66
cessation efforts, 13, 86–87, 103, 175
chronic sublethal damage from, 174, 253–54, 298
decrease in cancers related to, 200, 263–64
heart and lung disease and, 188–89, 265
popularity peak in United States, 265
proportion of cancer deaths attributable to, 266
secondhand smoke, 126
slimming effect of, 198
SMT. See somatic mutation theory (SMT)
solid organ and tissue cancers, 28, 80. See also specific cancer names
somatic mutation theory (SMT), 69–81. See also random accumulation hypothesis
defined, 70–71
denominator problem and, 100–101
environment and cancer risk and, 87–88, 106, 122, 124
fatal flaws in, 103–5
genetic diversity and, 153
genetic revolution, 69–75, 80–81
HER2/neu gene, 78–80
invasion and metastasis and, 242
natural selection and, 152
Philadelphia chromosome, 76–78
preposterous reductionism and, 107–8
reluctance to abandon, 127
revisions to, and failure of, 91–97, 105–6, 108
tumoral evolution and, 154, 156, 160–61
soot, 42–44
South Korea, 281–82
South Pacific Islanders, 188, 189–90, 203
specialization of cells, 135–36, 141–42
Special Virus Cancer Program (SVCP), 57–58, 61
speciation, 172–73
spontaneous regression, 294–97
src gene, 30, 70, 174
Stein, Fred, 295–96
stem cell, 171–72
stomach acid, 175
stomach cancer, 62–64, 90, 122, 199, 266
Strabo, 44
Streptococcus bacteria, 295, 296
Streptomyces hygroscopicus, 217, 219
stroke, 197, 211, 265
sugar, 87, 203–4, 213, 215, 287. See also carbohydrates, dietary; glucose
sulfonylurea drugs, 207
sunlight exposure, 194
surgery, 19–21, 176, 243–44, 245
surrogate outcomes, 112–15
Swedish Obese Subjects Study (SOS), 286
Swiss Medical Board, 273
tail, human, 164–65
Taleb, Nassim Nicholas, 94
tamoxifen, 176
Tannenbaum, Albert, 200–201
targeted antibodies, 25, 79
T cells, 301–4
telomerase, 33
telomeres, 33, 138, 176–77
Terry, Luther, 265
testicular cancer, 24
thalidomide, 117
thyroid cancer, 199, 268, 281–82, 285
tisagenlecleucel, 304
tissue architecture, 176–77
tobacco, 41–42, 46, 185–86, 265. See also smoking
Toronto Polyp Prevention Trial, 187
transformation, 119–81
cancerous transformation, 169–81
evolutionary model and, 249, 253–54
genetics, environment, and developing new paradigms, 121–31
origins of life and origins of cancer, 133–49
tumoral evolution, 151–68
trastuzumab, 78, 79–81, 106, 159
treatments for cancer. See also cancer prevention and screening; chemotherapy; dietary determinants of cancer; immunotherapy; radiation; surgery
ancient, 18
efficacy of, 11–13
excessive growth and, 19
hormonal, 159, 257, 308
resistance to, 257, 258–59
toxicity of, 274, 283, 304
tumoral evolution and, 157–60
“Trends in Incidence of Cancers Associated with Overweight and Obesity” (CDC), 198
TREX1, 307
tuberculosis (TB), 160–61, 300
tumoral evolution, 151–68
atavism, 164–68
branched-chain evolution, 154–57, 254
cancerous transformation, 169–81
convergent evolution, 162–64, 168
intratumoral heterogeneity (ITH), 153, 155, 159
natural and artificial selection, 151–52
selective pressure, 152, 157, 160–61, 171, 246–48, 254
self-seeding and, 245–49, 256
therapeutic implication, 157–60
tumor necrosis factor (TNF) alpha, 289
tumor-promoting inflammation, 35
tumors, 16, 19–20, 29–30, 34, 55, 112–13
tumor suppressor genes
discovery and definition of, 29–30, 70, 129
DNA methylation and, 123
growth control and, 137
junction of unicellular and multicellular life and, 170–71, 252
metabolic pathways and, 234
mutations in, 30–31, 70, 71, 72, 171, 174
twin studies, 83–85
two-hit hypothesis, 94
type 2 diabetes
cancer and, 203–6, 215
dietary prevention of cancer and, 286, 292
epidemic of, 5–6
glucose levels and, 233
green tea and, 291–92
insulin/IGF-1 and, 224, 287
intermittent fasting and, 290
metformin treatment and reduced cancer risk, 291
obesity and, 197, 201, 203, 205
traditional vs. Western lifestyles and, 186, 203–304
tyrosine kinases, 234
unicellular organisms
ancient existential threats and, 176
autonomy and, 143
cancer and reversion to existence of, 148–49, 159–61, 167–68, 169–73, 179–80, 237, 252–54
competition for resources and, 145, 148
death of, 222
exponential growth by, 144
genomic instability and, 146–47
hydra evolved from, 130
invasion of new environments, 143–44, 239
local destructiveness of, 143–44, 237
multicellular organisms compared to, 135–41, 251–52
nutrient availability and growth of, 212–13
specialization and, 141
United Kingdom, 207, 209
University of Texas MD Anderson Cancer Center, 110
uranium, 47–48
U.S. Congress Office of Technology Assessment, 185
U.S. Department of Agriculture (USDA), 126
U.S. Preventive Services Task Force (USPSTF), 271, 278, 279, 280–81
Utah Obesity Study, 286–87
vaccines
for bladder cancer treatment, 300–301
for the prevention of virus-caused cancers, 57, 59, 61, 267, 269
spontaneous regression and, 295
viral hepatitis and needles reused for, 58–59, 60
Varmus, Harold, 70
vascular endothelial growth factor (VEGF), 235
Venter, Craig, 92
ventricular ectopy, 112
viral hepatitis, 58–60
viruses, 134, 298. See also specific virus names
viruses and bacteria, cancers caused by, 53–65
Burkitt’s lymphoma, 53–56
cervical cancer, 60–61
decline in, 200, 266–67
genetic mutations and, 72–73
hepatitis B and C, 58–60, 266–67
nasopharyngeal cancer, 56–57
PI3K and, 211–12
Special Virus Cancer Program, 57–58, 61
stomach cancer, 62–64, 65, 90, 122, 174
Vitamin D and Omega-3 Trial (VITAL), 194–95
Vitamin D Assessment Study (ViDa), 195
Vitamin E Cancer Prevention Trial (SELECT), 195
vitamins, 190–95. See also folic acid (Vitamin B9)
Vogelstein, Bert, 94–95, 96
von Hippel–Lindau tumor suppressor gene, 71
Warburg, Otto, 37, 229–34, 235
Warburg effect and Warburg revival
genetic revolution and waning of interest in, 233–34
glucose metabolism and, 37, 140–41, 229–33, 234, 238
as hallmark of cancer, 38
hypoxia-inducible factor 1 (HIF) and, 255
invasion and, 241
lactic acid and, 229–31, 235–38
war on cancer
developing new paradigms, 125–31
excessive growth, cancer as, and, 7–13, 180, 258, 293–94
genetic disease, cancer as, and, 9–10, 91–97, 118, 294
mortality rates and, 7–9, 263–64
radiation therapy and, 22
somatic mutation theory and, 75, 91–94, 106
in South Korea, 281
Special Virus Cancer Program and, 57
targeted medicine and, 158
as war on ourselves, 17
Warren, Robin, 62–64
Watson, James, 11
weight loss, 4–5, 6, 200–201, 286–88, 289, 292. See also cancer cachexia
Weinberg, Robert, 28–29, 35, 78, 105–6, 128–29, 236
Western Norway B Vitamin Intervention Trial (WENBIT), 192
white blood cells, 23, 136
Women’s Health Initiative, 190
World Health Organization (WHO), 46–47
wound healing, 30, 174, 176, 237
X-rays, 20–22. See also radiation
yeast, 137, 138–39, 144–45, 212–13