Li Lin, McCormack Amanda A, Nicholson Joshua M, Fabarius Alice, Hehlmann Ruediger, Sachs Rainer K, Duesberg Peter H
Department of Molecular and Cell Biology, Donner Laboratory, University of California Berkeley, Berkeley, CA 94720, USA.
Cancer Genet Cytogenet. 2009 Jan 1;188(1):1-25. doi: 10.1016/j.cancergencyto.2008.08.016.
The chromosomes of cancer cells are unstable, because of aneuploidy. Despite chromosomal instability, however, cancer karyotypes are individual and quasi-stable, as is evident especially from clonal chromosome copy numbers and marker chromosomes. This paradox would be resolved if the karyotypes in cancers represent chromosomal equilibria between destabilizing aneuploidy and stabilizing selection for oncogenic function. To test this hypothesis, we analyzed the initial and long-term karyotypes of seven clones of newly transformed human epithelial, mammary, and muscle cells. Approximately 1 in 100,000 such cells generates transformed clones at 2-3 months after introduction of retrovirus-activated cellular genes or the tumor virus SV40. These frequencies are too low for direct transformation, so we postulated that virus-activated genes initiate transformation indirectly, via specific karyotypes. Using multicolor fluorescence in situ hybridization with chromosome-specific DNA probes, we found individual clonal karyotypes that were stable for at least 34 cell generations-within limits, as follows. Depending on the karyotype, average clonal chromosome numbers were stable within +/- 3%, and chromosome-specific copy numbers were stable in 70-100% cells. At any one time, however, relative to clonal means, per-cell chromosome numbers varied +/-18% and chromosome-specific copy numbers varied +/-1 in 0-30% of cells; unstable nonclonal markers were found within karyotype-specific quotas of <1% to 20% of the total chromosome number. For two clones, karyotypic ploidies also varied. With these rates of variation, the karyotypes of transformed clones would randomize in a few generations unless selection occurs. We conclude that individual aneuploid karyotypes initiate and maintain cancers, much like new species. These cancer-causing karyotypes are in flexible equilibrium between destabilizing aneuploidy and stabilizing selection for transforming function. Karyotypes as a whole, rather than specific mutations, explain the individuality, fluidity, and phenotypic complexity of cancers.
由于非整倍体的存在，癌细胞的染色体是不稳定的。然而，尽管存在染色体不稳定性，但癌症核型却是个体性的且近乎稳定的，这一点尤其明显地体现在克隆染色体拷贝数和标记染色体上。如果癌症中的核型代表了不稳定的非整倍体与致癌功能的稳定选择之间的染色体平衡，那么这个悖论就能得到解决。为了验证这一假设，我们分析了新转化的人类上皮细胞、乳腺细胞和肌肉细胞的七个克隆的初始和长期核型。在引入逆转录病毒激活的细胞基因或肿瘤病毒SV40后，大约每10万个这样的细胞中会有1个在2 - 3个月时产生转化克隆。这些频率对于直接转化来说太低了，所以我们推测病毒激活的基因是通过特定的核型间接启动转化的。使用与染色体特异性DNA探针的多色荧光原位杂交技术，我们发现了个体克隆核型，这些核型在至少34个细胞世代内是稳定的——在一定范围内，具体如下。根据核型的不同，平均克隆染色体数在±3%的范围内稳定，染色体特异性拷贝数在70 - 100%的细胞中是稳定的。然而，在任何一个时间点，相对于克隆平均值，每个细胞的染色体数在0 - 30%的细胞中变化±18%，染色体特异性拷贝数变化±1；在小于总染色体数1%至20%的核型特异性配额内发现了不稳定的非克隆标记。对于两个克隆，核型倍性也有所变化。以这些变异率，除非发生选择，转化克隆的核型在几代内就会随机化。我们得出结论，个体非整倍体核型启动并维持癌症，这很像新物种。这些致癌核型处于不稳定的非整倍体与转化功能的稳定选择之间的灵活平衡中。作为一个整体的核型，而非特定的突变，解释了癌症的个体性、流动性和表型复杂性。
