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

Abstract

BackgroundA 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.ResultsHere 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.ConclusionsOur 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.

Inherent variability of cancer-specific aneuploidy generates metastases

“…This absence of precursors of metastases confirms previous results from others including us [43, 76, 77, 126, 127]. In addition our results confirm the predicted absence of precursors of the many non-metastatic variants with multiple aneusomies and with the same complexities as their metastatic counterparts (Figs.…”

“…But ploidy variation in cancer cells is typically not exactly even, and is another independent characteristic of cancer cells that may increase or decrease oncogenicity by changing the dosage of genes evenly and non-evenly [76, 77, 112–114]. Its occurrence also seems to be proportional to the degree of cancer-specific aneuploidy [76, 115].…”

“…This proposal is based on the absence of the many intermediates or precursors predicted by the linear model, which are probably absent, because they are not viable [43, 76, 77, 125–127] and the finding of others that all aneusomies of the cancers analyzed carried genetic markers only from one, instead of both sets of normal parental chromosomes of an organism [128, 129]. …”

“…In searching for these elusive metastasis-genes, it was also observed that the proclivity of cancers to metastasize is determined prior to metastasis, is “preordained” [69] or “predetermined” [74]. Considering the elusive search for metastasis-genes and our prior work on the karyotypic basis of cancer and metastasis [43, 75–77] we have asked here, whether the proclivity of cancers to metastasize might be determined by cancer-specific aneuploidy.…”

“…Most such random variants perish. Rare karyotypic variants, however, form new autonomous cancer species with near-diploid, hypo-diploid or hyper-diploid karyotypes at very low rates, r3, because the probability to form a new autonomous cell is very low [75–77, 104, 105, 109, 135]. Owing to the inherent instability of aneuploidy, the karyotypes of new cancer species vary at aneuploidy-dependent rates, r2, within margins that are defined by selection for cancer-specific autonomy.…”