Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells

Abstract

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.

Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors

“…Fifth, this finding implies that a substantial portion of the phenotypic uniqueness (and by extension, the heterogeneity in clinical behavior) among patients' tumors may be traceable to underlying variation in DNA copy number. Sixth, this finding supports a possible role for widespread DNA copy number alteration in tumorigenesis (17,18), beyond the amplification of specific oncogenes and deletion of specific tumor suppressor genes. Widespread DNA copy number alteration, and the concomitant widespread imbalance in gene expression, might disrupt critical stochiometric relationships in cell metabolism and physiology (e.g., proteosome, mitotic spindle), possibly promoting further chromosomal instability and directly contributing to tumor development or progression.…”

Tetraploid State Induces p53-dependent Arrest of Nontransformed Mammalian Cells in G1

“…Given that inactivation of p53 in tetraploid cells results in progression toward aneuploidy, it is evident that tetraploid arrest may be an important means by which p53 preserves genomic integrity. Because aneuploidization is tightly correlated with tumor formation (Rabinovitch et al, 1989, Li et al, 1997Duesberg et al, 1998;Lengauer et al, 1998), we conclude that the tetraploidy checkpoint function of p53 may be essential to its role as a tumor suppressor.…”

“…Most human solid tumors are genetically unstable, and the loss or gain of complete chromosomes is the predominant form of genetic instability . Aneuploidy is an important element of tumorigenesis (Li et al, 1997), and inactivation of p53 is probably an important element of this process (Harvey et al, 1993). Because we show here that the inactivation of p53 in tetraploid cells results in aneuploidization following the completion of a single tetraploid cell cycle, and because the tetraploid state is a frequent precursor to aneuploidization in solid human tumors (Shackney et al, 1989), we propose that the prevention of aneuploidy by blocking the rereplication of tetraploid cells that result from failures in mitosis may be a vital function of p53.…”

Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma

“…Li et al 53 concluded that aneuploidy was the cause rather than a consequence of transformation, based on chromosome analysis of transformed cells. Duesberg et al 54 also showed that aneuploidy resulted in karyotypic and phenotypic heterogeneity of cancer cells.…”