Probabilistic view of the transformation of cultured C3H/10T1/2 mouse embryo fibroblasts by 3-methylcholanthrene.

Fernández, Alberto; Mondal, Shreya; Heidelberger, Charles

doi:10.1073/pnas.77.12.7272

Cited by 55 publications

(16 citation statements)

References 14 publications

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“…Within the following month most of these initial BP, MCA, and DMBA foci either disappeared or formed a homogenous background. The induction of apparently reversible hyperplasia by polycyclic hydrocarbons has been described previously for cells in culture (75)(76)(77)107) and also for cells in animals (78).…”

Section: Resultsmentioning

confidence: 99%

Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells

Yerganian

Duesberg

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

162

111

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Aneuploidy or chromosome imbalance is the most massive genetic abnormality of cancer cells. It used to be considered the cause of cancer when it was discovered more than 100 years ago. Since the discovery of the gene, the aneuploidy hypothesis has lost ground to the hypothesis that mutation of cellular genes causes cancer. According to this hypothesis, cancers are diploid and aneuploidy is secondary or nonessential. Here we reexamine the aneuploidy hypothesis in view of the fact that nearly all solid cancers are aneuploid, that many carcinogens are nongenotoxic, and that mutated genes from cancer cells do not transform diploid human or animal cells. By regrouping the gene pool-as in speciation-aneuploidy inevitably will alter many genetic programs. This genetic revolution can explain the numerous unique properties of cancer cells, such as invasiveness, dedifferentiation, distinct morphology, and specific surface antigens, much better than gene mutation, which is limited by the conservation of the existing chromosome structure. To determine whether aneuploidy is a cause or a consequence of transformation, we have analyzed the chromosomes of Chinese hamster embryo (CHE) cells transformed in vitro. This system allows (i) detection of transformation within 2 months and thus about 5 months sooner than carcinogenesis and (ii) the generation of many more transformants per cost than carcinogenesis. To minimize mutation of cellular genes, we have used nongenotoxic carcinogens. It was found that 44 out of 44 colonies of CHE cells transformed by benz[a]pyrene, methylcholanthrene, dimethylbenzanthracene, and colcemid, or spontaneously were between 50 and 100% aneuploid. Thus, aneuploidy originated with transformation. Two of two chemically transformed colonies tested were tumorigenic 2 months after inoculation into hamsters. The cells of transformed colonies were heterogeneous in chromosome number, consistent with the hypothesis that aneuploidy can perpetually destabilize the chromosome number because it unbalances the elements of the mitotic apparatus. Considering that all 44 transformed colonies analyzed were aneuploid, and the early association between aneuploidy, transformation, and tumorigenicity, we conclude that aneuploidy is the cause rather than a consequence of transformation.

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Section: Resultsmentioning

confidence: 99%

Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells

Yerganian

Duesberg

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

162

111

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“…One reason the role of mutations has been so difficult to assess is that in almost all transformation systems studied, if the endpoint is a cell capable of malignant growth, the process of cell transformation is the result of the sum of at least two steps (4,5,19,31,43). Sorting out the contribution of each step and the mechanism underlying each is only just beginning.…”

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confidence: 99%

Chemical carcinogens transform BHK cells by inducing a recessive mutation.

Bouck¹,

Mayorca²

1982

Mol. Cell. Biol.

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Treatment of BHK cells with mutagenic carcinogens induced neoplastic transformation in a single step. This transformation displayed the characteristics expected for a recessive mutation. Increasing doses of carcinogens induced transformants with kinetics similar to the kinetics with which they induced 6-thioguanine-resistant or ouabain-resistant mutants in the same population of cells. Transformants with temperature-restricted phenotypes were easily induced by carcinogens which cause mutations by base changes, but when ICR frameshift mutagens were used, the proportion of temperature-limited transformants was inversely related to the frequency with which a particular mutagen induced frameshift mutations. In hybrids between pseudodiploid isogenic strains of normal and transformed BHK cells, transformation was expressed as a dominant trait when the transformed parent was induced by a papovavirus, but was suppressed as a recessive trait when the transformed parent arose spontaneously or was chemically induced. Segregation of transformation was observed upon growth of suppressed normal hybrids, and the transformed phenotype which was reexpressed was in most cases characteristic of the original transformed parent.Although there is no controversy over the fact that mutagenic carcinogens can malignantly transform mammalian cells in vitro and in vivo (8,23) or over the fact that point mutations can be shown to accompany this transformation (30), whether mutations are necessary to malignantly transform a cell with a chemical carcinogen is still widely debated (11). One reason the role of mutations has been so difficult to assess is that in almost all transformation systems studied, if the endpoint is a cell capable of malignant growth, the process of cell transformation is the result of the sum of at least two steps (4,5,19,31,43). Sorting out the contribution of each step and the mechanism underlying each is only just beginning.There is however one cell system in which transformation can be induced to occur in a single step: the baby hamster kidney cell line BHK-21 clone 13 (BHK-21/cl 13) (9, 17, 51). This permanent cell line behaves as though the process of promotion or progression has already taken place. Only one additional event, the induction of anchorage independence, is needed to change BHK cells from nontumorigenic to tumorigenic (17); therefore, this transformation can be analyzed clearly and quantitatively. In experiments in which chemical carcinogens were used on a subclone of BHK cells (9), the frequency of spontaneous transformation, induced transformation, and reversion to normal and the occurrence of temperature-restricted transformants suggest that transformation is due to a somatic mutation. This paper provides more direct evidence for this assertion by demonstrating that mutation and transformation occur with parallel kinetics in response to increasing doses of carcinogens and that the type of transformants which are induced depend upon the type of mutations which the inducing carcinogen is capable of p...

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“…Effects are related to the number of transferred tumor cells. Cancer biology is chaotic and has numerous unknown steps, but the general opinion is that cancer is generated by malign transformation of a few or even only a single cell (Fernandez et al, 1980;Kennedy et al, 1980). Accordingly, whole cell type immunization may be more effective to prevent human cancers.…”

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confidence: 99%

Cancer Preventive Effects of Whole Cell Type Immunization against Mice Ehrlich Tumors

Ayşan

Bayrak²,

Aydemir³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Effects of whole cell type immunization on mice Ehrlich tumours were evaluated. Materials and Methods: After preliminary study, mice were divided two major groups; 1x1000 and 100x1000 live Ehrlich cell transferred major groups, each divided into four subgroups (n: 10). Study groups were immunized with Ehrlich cell lysates in 0, 3, 7, 14 th days and after 30 days of last immunization, live Ehrlich cells were transferred. Mice were observed for six months and evaluated for total and cancer free days. Results: Out of 100x1000 cell transferred solid type study group, all study group mean and tumour free periods were statistically longer than control groups. All 1x1000 Ehrlich cell transferred study groups survived significantly longer than 100x1000 Ehrlich cell transferred groups. Conclusions: Ehrlich mice tumours were prevented and survival prolonged with whole cell type immunization. Effects are related to the number of transferred tumor cells.

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Probabilistic view of the transformation of cultured C3H/10T1/2 mouse embryo fibroblasts by 3-methylcholanthrene.

Cited by 55 publications

References 14 publications

Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells

Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells

Chemical carcinogens transform BHK cells by inducing a recessive mutation.

Cancer Preventive Effects of Whole Cell Type Immunization against Mice Ehrlich Tumors

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