The age distribution of cancer and a multi-stage theory of carcinogenesis

Armitage, P.; Doll, Richard

doi:10.1038/sj.bjc.6602297

Cited by 712 publications

(479 citation statements)

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“…In addition, tissues with a high self-renewal capacity are known to give rise to cancer even a million times more often than tissues without this capacity [12]. Recent analyses of the stinking differences in cancer risk by age and among tissues indicate that the main biological cause of cancer is the accumulation of cell divisions in stem cells [12][13][14][15][16]. The marked increase in cancer incidence with age observed for most cancers [11] strongly suggests that cancer originates in stem cells ( Figure 1) [14,15].…”

Section: Discussionmentioning

confidence: 99%

A local mechanism by which alcohol consumption causes cancer

López‐Lázaro

2016

Oral Oncology

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Epidemiological data indicate that 5.8% of cancer deaths world-wide are attributable to alcohol consumption. The risk of cancer is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. The risk of these cancers is increased even in people who have only one alcoholic drink per day. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mostly produced in the liver, it is not clear why alcohol use preferentially exerts a local carcinogenic effect. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages; however, this effect has been overlooked probably because dead cells cannot give rise to cancer. Here I discuss that the cytotoxic effect of ethanol on the cells lining the oral cavity, pharynx and esophagus activates the division of the stem cells located in deeper layers of the mucosa to replace the dead cells. Every time stem cells divide, they become exposed to unavoidable errors associated with cell division (e.g., mutations arising during DNA replication and chromosomal alterations occurring during mitosis) and also become highly vulnerable to the genotoxic activity of endogenous and exogenous DNA-damaging agents (e.g., reactive oxygen species, acetaldehyde and tobacco carcinogens). Alcohol consumption probably increases the risk of developing cancer of the oral cavity, pharynx and esophagus by promoting the accumulation of cell divisions in the stem cells that maintain these tissues in homeostasis. Because the cytotoxic activity of ethanol is concentration-dependent, the risk of these cancers will not only increase with increasing amounts of ethanol, but also with increasing concentrations; an ounce of whisky is probably more carcinogenic when taken undiluted than when taken mixed with non-alcoholic beverages. The local cytotoxic effect of ethanol can also explain the known synergistic effect of alcohol and tobacco use on the risk of these cancers. Understanding the mechanisms of carcinogenicity of alcohol is important to reinforce the epidemiological evidence and to raise public awareness of the strong link between alcohol consumption and cancer.

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Section: Discussionmentioning

confidence: 99%

A local mechanism by which alcohol consumption causes cancer

López‐Lázaro

2016

Oral Oncology

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“…The precise mechanism underlying the dramatic age-related rise of cancer remains unclear, but the importance of mutation in cancer presents a likely explanation (Knudson, 2001). It is hypothesized that a small number of genetic events -causing either activation of oncogenes or inactivation of tumor suppressor genes -precede each stage of tumorigenesis (Armitage, 1954;Armitage, 1957;Knudson, 2001). By middle age, sufficient cellular genomic damage may have accumulated to initiate carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Does age influence loss of heterozygosity?

Carr

Gottschling

2008

Experimental Gerontology

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The striking correlation between advanced age and an increased incidence of cancer has led investigators to examine the influence of aging on genome maintenance.Because loss of heterozygosity (LOH) can lead to the inactivation of tumor suppressor genes, and thus carcinogenesis, understanding the affect of aging on this type of mutation event is particularly important. Several factors may affect the rate of LOH, including an increase in the amount of DNA damage, specifically double-strand breaks (DSB), and the ability to efficiently repair this damage via pathways that minimize the loss of genetic information. Because of experimental constraints, there is only suggestive evidence for a change in the rate of DNA damage as humans age. However, recent studies in model organisms find that there are increased rates of LOH with age, and that repair of DNA damage occurs via a different pathway in old cells versus young cells. We speculate that the age-dependent change in DNA repair may explain why there is increased LOH, and that the findings from these model organisms may extend to humans.

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“…The best news about cancer is that we and other animals are all born cancer-free and typically acquire cancer, if at all, only at advanced age [34,[36][37][38][39][40]. This bias of cancer for old age is exponential, increasing the cancer risk 300-fold with age, from near-zero rates in newborns and adolescents to rates of 1 in 3 in the last third of a human or animal life span ( fig.…”

Section: Cancer Is Not Heritablementioning

confidence: 99%

Aneuploidy and Cancer: From Correlation to Causation

Duesberg

Fabarius³

et al. 2006

Infection and Inflammation: Impacts on Oncogenesis

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Conventional genetic theories have failed to explain why cancer (1) is not found in newborns and thus not heritable; (2) develops only years to decades after 'initiation' by carcinogens; (3) is caused by non-mutagenic carcinogens; (4) is chromosomally and phenotypically 'unstable'; (5) carries cancer-specific aneuploidies; (6) evolves polygenic phenotypes; (7) nonselective phenotypes such as multidrug resistance, metastasis or affinity for non-native sites and 'immortality' that is not necessary for tumorigenesis; (8) contains no carcinogenic mutations. We propose instead that cancer is a chromosomal disease: Accordingly, carcinogens initiate chromosomal evolutions via unspecific aneuploidies. By unbalancing thousands of genes aneuploidy corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is thus a steady source of karyotypic-phenotypic variations from which, in classical Darwinian terms, selection of cancer-specific aneuploidies encourages the evolution and subsequent malignant 'progressions' of cancer cells. The rates of these variations are proportional to the degrees of aneuploidy, and can exceed conventional mutation by 4-7 orders of magnitude. This makes cancer cells new cell 'species' with distinct, but unstable karyotypes, rather than mutant cells. The cancer-specific aneuploidies generate complex, malignant phenotypes, through the abnormal dosages of the thousands of genes, just as trisomy 21 generates Down syndrome. Thus cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) nonheritability of cancer, because aneuploidy is not heritable; (2) long 'neoplastic latencies' by the low probability of evolving competitive new species; (3) nonselective phenotypes via genes hitchhiking on selective chromosomes, and (4) 'immortality', because chromosomal variations neutralize negative mutations and adapt to inhibitory conditions much faster than conventional mutation. Based on this article a similar one, entitled 'The chromosomal basis of cancer', has since been published by us in Cellular Oncology 2005;27:293-318. Copyright © 2006 S. Karger AG, Basel Despite over 100 years of cancer research, the cause of cancer is still a matter of debate . We propose here that the problem of cancer is still

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The age distribution of cancer and a multi-stage theory of carcinogenesis

Cited by 712 publications

References 7 publications

A local mechanism by which alcohol consumption causes cancer

A local mechanism by which alcohol consumption causes cancer

Does age influence loss of heterozygosity?

Aneuploidy and Cancer: From Correlation to Causation

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