Immortality of cancers

Abstract

Immortality is a common characteristic of cancers, but its origin and purpose are still unclear. Here we advance a karyotypic theory of immortality based on the theory that carcinogenesis is a form of speciation. Accordingly, cancers are generated from normal cells by random karyotypic rearrangements and selection for cancer-specific reproductive autonomy. Since such rearrangements unbalance long-established mitosis genes, cancer karyotypes vary spontaneously but are stabilized perpetually by clonal selections for autonomy. To test this theory we have analyzed neoplastic clones, presumably immortalized by transfection with overexpressed telomerase or with SV40 tumor virus, for the predicted clonal yet flexible karyotypes. The following results were obtained: (1) All immortal tumorigenic lines from cells transfected with overexpressed telomerase had clonal and flexible karyotypes; (2) Searching for the origin of such karyotypes, we found spontaneously increasing, random aneuploidy in human fibroblasts early after transfection with overexpressed telomerase; (3) Late after transfection, new immortal tumorigenic clones with new clonal and flexible karyotypes were found; (4) Testing immortality of one clone during 848 unselected generations showed the chromosome number was stable, but the copy numbers of 36% of chromosomes drifted ± 1; (5) Independent immortal tumorigenic clones with individual, flexible karyotypes arose after individual latencies; (6) Immortal tumorigenic clones with new flexible karyotypes also arose late from cells of a telomerase-deficient mouse rendered aneuploid by SV40 virus. Because immortality and tumorigenicity: (1) correlated exactly with individual clonal but flexible karyotypes; (2) originated simultaneously with such karyotypes; and (3) arose in the absence of telomerase, we conclude that clonal and flexible karyotypes generate the immortality of cancers.

HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution

“…The aberrant karyotype, genomic heterogeneity, and constitutive expression of adenoviral E1 gene make transcriptome of 293 cells severely deregulated, bringing to naught affords to elucidate an authentic cell type of origin and present phenotype. It should be noted that all immortalized cell lines irrespectively of an "immortalizing agent" (viral genomes/ oncogenes, telomerase reverse transcriptase catalytic subunit (TERT), transcription factors, chemical treatment or spontaneously) are characterized by abnormal karyotypes, and genome alterations are essential for cellular immortalization, transformation, metastasis and drug resistance (Duesberg et al, 2011(Duesberg et al, , 2012Duesberg and McCormack, 2013;Heng et al, 2010Heng et al, , 2011Heng et al, , 2013Kavsan, 2012, 2013). The different types of stress (such as over-or under-expression of oncogenes or tumor suppressor genes, drug treatment, medium growth changes, and other experimental manipulations) can trigger/promote genome instability and the generation of population diversity through the combination of clonal and non-clonal chromosomal aberrations, epigenetic and nongenetic heterogeneity.…”

Necrosis, and then stress induced necrosis-like cell death, but not apoptosis, should be the preferred cell death mode for chemotherapy: clearance of a few misconceptions

“…Sporadic tumorigenesis, a process for the development of a benign or a malignant sporadic tumor, starts with immortalization of one somatic cell [ 10 ], which likely involves alteration in genomic DNA. Here, “immortality” does not mean that the immortalized cell itself is immortal, but, instead, it means that the cellular death program has been reprogrammed to allow the cell to divide for limitless rounds, much over the Hayflick limit that is about 50 generations in vitro [ 11 - 13 ]. In our rumination, this reprogramming revokes the legality of immortalized cell lines in exploration of apoptosis mechanisms, because the identified “mechanisms” cannot reflect the true apoptosis programs in the cells of a living animal [ 1 , 7 ].…”

Cancer Karyotypes: Survival of the Fittest

“…The adaptive potential of aneuploidy in yeast is well demonstrated for many other exogenous stresses (Selmecki et al, 2006, 2009; Pavelka et al, 2010; Tang et al, 2011; Rancati and Pavelka, 2013). Aneuploidy has also been proposed as a mechanism that can counteract the accumulation of deleterious mutations, a process termed Muller’s Ratchet (Muller, 1964; Bignold, 2007a,b; Torres et al, 2008; Vincent, 2011; Duesberg and McCormack, 2013). An elegant study by Rancati et al (2008) supports this idea showing that aneuploidy can rescue deleterious mutations in a conserved cytokinesis motor.…”