Is cancer progression caused by gradual or simultaneous acquisitions of new chromosomes?

Abstract

BackgroundFoulds defined, “Tumor progression (as a) permanent, irreversible qualitative change in one or more of its characters” (Cancer Res. 1954). Accordingly progressions, such as metastases and acquired drug-resistance, were since found to be subspecies of cancers with conserved and numerous new chromosomes. Here we ask whether cancers acquire numerous new chromosomes gradually or simultaneously in progressions. The currently prevailing theory of Nowell (Science, 1976) holds that unexplained “genetic instability” generates “variant sublines (with) changes in chromosome number” and that “clonal” progressions arise by “stepwise selection of more aggressive sublines”. The literature, however, contains many examples of “immediate” selections of progressions with numerous new chromosomes - notably experimentally initiated fusions between cancers and heterologous cells. Furthermore, the stepwise progression theory predicts intermediate sublines of cancers with multiple non-clonal additions of new chromosomes. However, the literature does not describe such intermediates.ResultsIn view of these inconsistencies with stepwise progression we test here a saltational theory, in which the inherent variability of cancer-specific aneuploidy generates “immediate” progressions with individual clonal karyotypes, transcriptomes and phenotypes in single steps. Using cell fusion as an established controllable model of “immediate” progression, we generated seven immortal murine hybridomas by fusing immortal murine myeloma cells and normal antibody-producing B-cells with polyethylene glycol within a few minutes. These immortal hybridomas contained individual sets of 71 to 105 clonal chromosomes, compared to the 52 chromosomes of the parental myeloma. Thus the myeloma had gained 19 to 53 new clonal chromosomes in seven individual hybridomas in a single step. Furthermore, no stable intermediates were found, as would be predicted by a saltational process.ConclusionsWe conclude that random fusions between myelomas and normal B-cells generate clonal hybridomas with multiple, individual chromosomes in single steps. Similar single-step mechanisms may also generate the “late” clonal progressions of cancers with gains of numerous new chromosomes and thus explain the absence of intermediates. Latency would reflect the low probability of rare stochastic progressions. In conclusion, the karyotypic clonality of hybridomas and spontaneous progressions suggests karyotypic alterations as proximate causes of neoplastic progressions. Since cancer-specific aneuploidy catalyzes karyotypic variation, the degree of aneuploidy predicts the clinical risk of neoplastic progression, confirming classical predictions based on DNA content.

Anaplastic lymphoma kinase fusions: Roles in cancer and therapeutic perspectives (Review)

“…To address this complexity, additional ad hoc explanations have been postulated, and carcinogenesis is thought to represent a problem of tissue organization on the basis of tissue organization field theory (101)(102)(103). According to recent studies, chromosomal aberration-mediated genome evolution is responsible for all major transitions in cancer evolution, including phenotypic plasticity, metastasis and drug resistance (104,105). It is believed that the genome serves as the evolutionary platform that links gene/epigene interaction and multiple levels of omics, which can be driven by genome-level alteration rather than individual hallmarks as gene mutation or epigenetic alteration.…”

Molecular Cytogenetic Characterization of Two Murine Colorectal Cancer Cell Lines

“…Overall, both cell lines showed clonal changes in common and in general had a tendency for ongoing karyotypic evolution [4,21]. Additionally, it must be mentioned that the studied cell lines were established about 40 years ago and have been passaged many times since then.…”

Speciation Theory of Carcinogenesis Explains Karyotypic Individuality and Long Latencies of Cancers

“…According to the speciation theory carcinogens initiate cancer by aneuploidization, which automatically unbalances thousands of genes and thus catalyzes chain reactions of progressive aneuploidizations [ 5 , 10 , 45 , 58 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Over time, these aneuploidizations have two endpoints, either non-viable karyotypes or very rarely karyotypes of a new autonomous cancer cell [ 5 , 55 , 71 ] ( Figure 1 ). The low probability that random aneuploidizations generate a new autonomous cancer (or other species) explains why cancers have individual clonal karyotypes and are typically late [ 5 , 14 , 40 , 55 , 71 , 72 , 73 , 74 , 75 ].…”

“…Over time, these aneuploidizations have two endpoints, either non-viable karyotypes or very rarely karyotypes of a new autonomous cancer cell [ 5 , 55 , 71 ] ( Figure 1 ). The low probability that random aneuploidizations generate a new autonomous cancer (or other species) explains why cancers have individual clonal karyotypes and are typically late [ 5 , 14 , 40 , 55 , 71 , 72 , 73 , 74 , 75 ]. The karyotypes of new autonomous cancer cells are stabilized and immortalized, despite destabilizing congenital aneuploidy, by clonal selection for autonomy and immortality [ 5 , 41 ] ( Figure 1 ).…”