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Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea

BACKGROUND: A century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes. Since speciation from known precursors also depends on long latencies and new species also have individual kar...

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Autores principales: Bloomfield, Mathew, McCormack, Amanda, Mandrioli, Daniele, Fiala, Christian, Aldaz, C Marcelo, Duesberg, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302718/
https://www.ncbi.nlm.nih.gov/pubmed/25614763
http://dx.doi.org/10.1186/s13039-014-0071-x
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author Bloomfield, Mathew
McCormack, Amanda
Mandrioli, Daniele
Fiala, Christian
Aldaz, C Marcelo
Duesberg, Peter
author_facet Bloomfield, Mathew
McCormack, Amanda
Mandrioli, Daniele
Fiala, Christian
Aldaz, C Marcelo
Duesberg, Peter
author_sort Bloomfield, Mathew
collection PubMed
description BACKGROUND: A century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes. Since speciation from known precursors also depends on long latencies and new species also have individual karyotypes, we and others have recently proposed that carcinogenesis is a form of speciation. According to this theory karyotypic evolutions generate new cancer species from normal cells as follows: Carcinogens induce aneuploidy (Figure 1). By unbalancing thousands of genes aneuploidy automatically destabilizes the karyotype and thus catalyzes random karyotypic variations. Selections of variants with proliferative phenotypes form non-clonal hyperplasias with persistently varying karyotypes. Very rare karyotypic variations form new cancer species with individual clonal karyotypes. Despite destabilization by the resulting congenital aneuploidies, cancer karyotypes are stabilized within narrow margins of variation by clonal selections for cancer-specific autonomy. Because all non-cancerous aneuploidies are unstable, all aneusomies of prospective cancers are joined in single-steps, rather than gradually. Since this mechanism is very inefficient, it predicts long latent periods from carcinogens to cancers and individual clonal cancer karyotypes. RESULTS: Here we have tested the predicted roles of karyotypic evolutions during the time course of carcinogenesis in an established experimental system. In this system injection of nitrosourea induces in female rats non-invasive mammary hyperplasias (“tumors”) after two or more months, and invasive carcinomas after six or more months. Accordingly four specific predictions were tested: (1) Invasive cancers are late and carry individual clonal karyotypes and phenotypes, (2) Persistent hyperplasias carry non-clonal karyotypes, (3) Non-clonal hyperplasias generate clonal cancers spontaneously but rarely, (4) Cancer-karyotypes arise with all individual clonal aneusomies in single-steps. All four predictions were experimentally confirmed. CONCLUSIONS: Our results along with the literature reveal a coherent karyotypic mechanism of carcinogenesis: Carcinogens induce aneuploidy. The inherent instability of aneuploidy automatically catalyzes new karyotypic variations. Aneuploid karyotypes with proliferative phenotypes form varying non-clonal hyperplasias. Rare variations form cancer species with individual clonal karyotypes, which are stabilized by clonal selection for autonomy. The low odds of this mechanism explain the long latencies of carcinogenesis, the individuality and karyotypic clonality of cancers.
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spelling pubmed-43027182015-01-23 Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea Bloomfield, Mathew McCormack, Amanda Mandrioli, Daniele Fiala, Christian Aldaz, C Marcelo Duesberg, Peter Mol Cytogenet Research BACKGROUND: A century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes. Since speciation from known precursors also depends on long latencies and new species also have individual karyotypes, we and others have recently proposed that carcinogenesis is a form of speciation. According to this theory karyotypic evolutions generate new cancer species from normal cells as follows: Carcinogens induce aneuploidy (Figure 1). By unbalancing thousands of genes aneuploidy automatically destabilizes the karyotype and thus catalyzes random karyotypic variations. Selections of variants with proliferative phenotypes form non-clonal hyperplasias with persistently varying karyotypes. Very rare karyotypic variations form new cancer species with individual clonal karyotypes. Despite destabilization by the resulting congenital aneuploidies, cancer karyotypes are stabilized within narrow margins of variation by clonal selections for cancer-specific autonomy. Because all non-cancerous aneuploidies are unstable, all aneusomies of prospective cancers are joined in single-steps, rather than gradually. Since this mechanism is very inefficient, it predicts long latent periods from carcinogens to cancers and individual clonal cancer karyotypes. RESULTS: Here we have tested the predicted roles of karyotypic evolutions during the time course of carcinogenesis in an established experimental system. In this system injection of nitrosourea induces in female rats non-invasive mammary hyperplasias (“tumors”) after two or more months, and invasive carcinomas after six or more months. Accordingly four specific predictions were tested: (1) Invasive cancers are late and carry individual clonal karyotypes and phenotypes, (2) Persistent hyperplasias carry non-clonal karyotypes, (3) Non-clonal hyperplasias generate clonal cancers spontaneously but rarely, (4) Cancer-karyotypes arise with all individual clonal aneusomies in single-steps. All four predictions were experimentally confirmed. CONCLUSIONS: Our results along with the literature reveal a coherent karyotypic mechanism of carcinogenesis: Carcinogens induce aneuploidy. The inherent instability of aneuploidy automatically catalyzes new karyotypic variations. Aneuploid karyotypes with proliferative phenotypes form varying non-clonal hyperplasias. Rare variations form cancer species with individual clonal karyotypes, which are stabilized by clonal selection for autonomy. The low odds of this mechanism explain the long latencies of carcinogenesis, the individuality and karyotypic clonality of cancers. BioMed Central 2014-12-16 /pmc/articles/PMC4302718/ /pubmed/25614763 http://dx.doi.org/10.1186/s13039-014-0071-x Text en © Bloomfield et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Bloomfield, Mathew
McCormack, Amanda
Mandrioli, Daniele
Fiala, Christian
Aldaz, C Marcelo
Duesberg, Peter
Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
title Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
title_full Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
title_fullStr Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
title_full_unstemmed Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
title_short Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
title_sort karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302718/
https://www.ncbi.nlm.nih.gov/pubmed/25614763
http://dx.doi.org/10.1186/s13039-014-0071-x
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