A new theory of carcinogenesis

Holliday, Robin

doi:10.1038/bjc.1979.216

Cited by 191 publications

(59 citation statements)

References 44 publications

(35 reference statements)

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“…The effects of 5-azaC on the proliferative features of the three lines suggest that changes in methylation patterns have a central role in the generation of biological diversity. Such diversity may on the other hand be a necessary feature of malignant behavior (26, 32) as well as it is conceivable that demethylation is an important event in oncogenesis (33). It was also recently demonstrated that demethylation of certain genes in the murine Lewis lung tumor system may lead to metastatic activity of otherwise nonmetastatic cells (34).…”

Section: Discussionmentioning

confidence: 99%

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate.

Olsson¹,

Due²,

Diamant³

1985

The Journal of Cell Biology

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Liquid medium cultures of three human cell lines (B-lymphoma, myeloma, and squamous lung carcinoma) with population-doubling times (PDT) and cloning efficiencies (CE) in the range of 32-43 h and 0.01-5.6%, respectively, were exposed to 5-azacytidine (5-azaC) for 3 d. The doses used (1-3/zM) were found to be nontoxic as measured by cell growth in liquid and semisolid agar medium and to be nonmutagenic as measured by the rate of generation of ouabain-and 6-thioguanine-resistant cell variants. After 5-azaC treatment, cell samples were subsequently harvested every day and assayed for their CE in semisolid agar medium. For each cell line, 30 to 42 individual clones were harvested at the day of maximal CE and expanded in liquid culture medium. PDT and CE were determined for each subclone about every 6 wk for 12 too. The majority of the subclones had unaltered PDT and CE compared to the original lines. However, several clones had profoundly changed proliferative activity with PDT on ~12-14 h and/or CE 5 to >50%. Some of the clones with altered growth properties reverted to PDT and/or CE values of untreated clones. However, a few clones of each line had stable alterations with PDT on 12-14 h and CE 5 to >50%; these clones were all significantly hypomethylated. It is concluded that the human gene repertoire does contain genes that appropriately activated can result in growth properties with very short PDT and high CE (and comparable to animal cell lines), and that this activation may be obtained by 5-azaC treatment. It is conceivable that the procedure here described to alter growth properties of human cell lines may be applied to experimental situations, where alterations of cell growth properties are desired.Many reports in recent years on regulation of both cellular 0-6) and viral~ genes (7-11) have provided experimental support to the hypothesis (12-15) that 5-methylcytosine (mSCyt) t may be important in the regulation of gene expression. Moreover, a number of experiments have shown that exposure of cells to 5-azacytidine (5-azaC) may result in hypomethylation of DNA and cause expression of otherwise silent genes of both cellular and viral origin (for review, cf. references 16, 17) to the extent that it mimics mutation induced genetic alterations, e.g., reversion frequency of thyAbbreviations used in this paper." 5-azaC, 5-azacytidine; CE, cloning efficiency; mSCyt, 5-methylcytosine; Oua r, ouabin resistant; PDT, population-doubling time; RPMI/FCS, RPMI-1640 medium SUlSplemerited with 0.3% L-glutamine and 10-15% fetal calf serum; 6-TG ~, 6-thioguanine resistant. midine kinase negative cells to thymidine kinase positive cells (18).The growth properties of malignant tumor cell lines are at least in part reflected in the growth rate and CE. However, it has hitherto not been possible by exogenous factors to alter profoundly these biological features, despite numerous attempts that mainly have been based on alterations in the growth medium conditions such as addition of growth factors like insulin and transferr...

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Section: Discussionmentioning

confidence: 99%

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate.

Olsson¹,

Due²,

Diamant³

1985

The Journal of Cell Biology

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“…These results suggest that hypomethylation of DNA may provide a common transforming mechanism shared by chemical carciidogens and oncogenic viruses. Genetic vs. epigenetic considerations A purely epigenetic model of carcinogenesis, also concerned with the effects of hypomethylation upon cell populations, has been put forward (Holliday, 1979). This model proposes that damage to DNA results in the potentially reversible loss of methyl groups as a function of repair processes.…”

Section: -Mc Depletion During Tumour Developmentmentioning

confidence: 99%

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

Nyce¹,

Weinhouse²,

Magee³

1983

Br J Cancer

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Perhaps the most ubiquitous aspect of tumours and the neoplastic cells of which they are composed is their loss of the ability to control cellular functions in a normal way. During the development of the malignant state, the neoplastic cell becomes increasingly refractory to both the internal and external stimulae which integrate its normal counterparts into functional tissues and organ systems. This lack of integration is associated with alterations in the expression of a host of gene products, including, for example, the ectopic biosynthesis of hormones (

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“…In the case of a genetic programme, the explanation is easy: Mutation, or an epigenetic change in gene regulation (Holliday 1979), may simply interrupt the programme. Most carcinogens are, after all, potent mutagens.…”

Section: "Immortalisation" Of Transformed Cellsmentioning

confidence: 99%

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

1982

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Summary. Cytogerontology, the science of cellular ageing, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential. Weismann's prediction was derived by considering the role of natural selection in regulating the duration of an organism's life. For various reasons, Weismann's ideas on ageing fell into neglect following his death in 1914, and cytogerontology has only reappeared as a major research area following'the demonstration by Hayflick and Moorhead in the early 1960s that diploid human fibroblasts are restricted to a finite number of divisions in vitro.In this review we give a detailed account of Weismann's theory, and we reveal that his ideas were both more extensive in their scope and more pertinent to current research than is generally recognised. We also appraise the progress which has been made over the past hundred years in investigating the causes of ageing, with particular emphasis being given to (i) the evolution of ageing, and (ii) ageing at the cellular level. We critically assess the current state of knowledge in these areas and recommend a series of points as primary targets for future research.

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A new theory of carcinogenesis

Cited by 191 publications

References 44 publications

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate.

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate.

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

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