Duesberg P, Rausch C, Rasnick D, Hehlmann R
III Medizinische Klinik Mannheim of the University of Heidelberg, Wiesbadener Strasse 7-11, Mannheim, D 68305 Germany.
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13692-7. doi: 10.1073/pnas.95.23.13692.
Genetic and phenotypic instability are hallmarks of cancer cells, but their cause is not clear. The leading hypothesis suggests that a poorly defined gene mutation generates genetic instability and that some of many subsequent mutations then cause cancer. Here we investigate the hypothesis that genetic instability of cancer cells is caused by aneuploidy, an abnormal balance of chromosomes. Because symmetrical segregation of chromosomes depends on exactly two copies of mitosis genes, aneuploidy involving chromosomes with mitosis genes will destabilize the karyotype. The hypothesis predicts that the degree of genetic instability should be proportional to the degree of aneuploidy. Thus it should be difficult, if not impossible, to maintain the particular karyotype of a highly aneuploid cancer cell on clonal propagation. This prediction was confirmed with clonal cultures of chemically transformed, aneuploid Chinese hamster embryo cells. It was found that the higher the ploidy factor of a clone, the more unstable was its karyotype. The ploidy factor is the quotient of the modal chromosome number divided by the normal number of the species. Transformed Chinese hamster embryo cells with a ploidy factor of 1.7 were estimated to change their karyotype at a rate of about 3% per generation, compared with 1.8% for cells with a ploidy factor of 0.95. Because the background noise of karyotyping is relatively high, the cells with low ploidy factor may be more stable than our method suggests. The karyotype instability of human colon cancer cell lines, recently analyzed by Lengnauer et al. [Lengnauer, C., Kinzler, K. W. & Vogelstein, B. (1997) Nature (London) 386, 623-627], also corresponds exactly to their degree of aneuploidy. We conclude that aneuploidy is sufficient to explain genetic instability and the resulting karyotypic and phenotypic heterogeneity of cancer cells, independent of gene mutation. Because aneuploidy has also been proposed to cause cancer, our hypothesis offers a common, unique mechanism of altering and simultaneously destabilizing normal cellular phenotypes.
遗传和表型不稳定性是癌细胞的标志，但其成因尚不清楚。主流假说是，一种定义不明的基因突变会导致遗传不稳定性，随后众多突变中的一些会引发癌症。在此，我们研究癌细胞的遗传不稳定性是由非整倍体（染色体的异常平衡）引起的这一假说。由于染色体的对称分离依赖于恰好两份有丝分裂基因拷贝，涉及有丝分裂基因的染色体的非整倍体将使核型不稳定。该假说预测，遗传不稳定性的程度应与非整倍体的程度成正比。因此，若要在克隆繁殖中维持高度非整倍体癌细胞的特定核型，即便并非不可能，也应十分困难。这一预测在化学转化的非整倍体中国仓鼠胚胎细胞的克隆培养中得到了证实。研究发现，克隆的倍性因子越高，其核型就越不稳定。倍性因子是众数染色体数除以该物种正常染色体数的商。据估计，倍性因子为1.7的转化中国仓鼠胚胎细胞，其核型每代变化率约为3%，而倍性因子为0.95的细胞为1.8%。由于核型分析的背景噪声相对较高，倍性因子低的细胞可能比我们的方法所显示的更稳定。Lengnauer等人[Lengnauer, C., Kinzler, K. W. & Vogelstein, B. (1997) Nature (London) 386, 623 - 627]最近分析的人类结肠癌细胞系的核型不稳定性，也与其非整倍体程度完全对应。我们得出结论，非整倍体足以解释癌细胞的遗传不稳定性以及由此产生的核型和表型异质性，而与基因突变无关。由于也有人提出非整倍体会引发癌症，我们的假说提供了一种改变并同时破坏正常细胞表型的共同且独特的机制。
