How aneuploidy affects metabolic control and causes cancer
How aneuploidy affects metabolic control and causes cancer
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DOI：
10.1042/0264-6021:3400621
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发表时间：
1999-06-15
影响因子：
4.1
通讯作者：
Duesberg, PH
中科院分区：
文献类型：
--
作者：
Rasnick, D;Duesberg, PH
癌症特异性表型的复杂性和多样性，包括去分化、侵袭性、转移、异常形态和代谢、遗传不稳定性和恶性进展，迄今为止还没有简单、一致的假说来解释。然而，《代谢控制分析》的改编支持了100年前的假设，即染色体数目异常的非整倍体是癌症的原因。这些结果证明了目前反直觉的原理，即控制表型转化的是经历差异表达的基因组的分数，而不是差异表达的幅度。将强健的正常表型转化为癌症需要数千种正常基因产物的表达增加两倍。基因剂量的巨大变化在细胞和组织的生理和代谢中产生高度非线性（即定性）变化。由于非整倍体破坏了有丝分裂蛋白的自然平衡，它也解释了癌细胞由于染色体的永久重组而引起的臭名昭著的遗传不稳定性。鉴于这一点以及非癌性非整倍体的存在，我们提出癌症是细胞的表型高于一定的非整倍体阈值。通过非整倍体水平的逐渐、逐步增加或通过四倍化随后染色体的逐渐丢失来达到该阈值，所述非整倍体水平是非整倍体细胞的自催化遗传不稳定性的结果。因此，癌发生的起始步骤产生低于癌症阈值的非整倍性，而促进步骤增加高于该阈值的非整倍性水平。我们的结论是，非整倍体提供了一个简单而连贯的解释所有的癌症特异性表型。因此，总体生化异常、异常的细胞大小和形态、肿瘤相关抗原的出现、负责侵袭性和接触抑制丧失的高水平分泌蛋白，以及甚至使癌细胞能够逃避化疗的令人生畏的遗传不稳定性，都是蛋白质大量过度表达和表达不足的自然结果。
The complexity and diversity of cancer-specific phenotypes, including de-differentiation, invasiveness, metastasis, abnormal morphology and metabolism, genetic instability and progression to malignancy, have so far eluded explanation by a simple, coherent hypothesis. However, an adaptation of Metabolic Control Analysis supports the 100-year-old hypothesis that aneuploidy, an abnormal number of chromosomes, is the cause of cancer. The results demonstrate the currently counter-intuitive principle that it is the fraction of the genome undergoing differential expression, not the magnitude of the differential expression, that controls phenotypic transformation. Transforming the robust normal phenotype into cancer requires a twofold increase in the expression of thousands of normal gene products. The massive change in gene dose produces highly nonlinear (i.e. qualitative) changes in the physiology and metabolism of cells and tissues. Since aneuploidy disrupts the natural balance of mitosis proteins, it also explains the notorious genetic instability of cancer cells as a consequence of the perpetual regrouping of chromosomes. In view of this and the existence of non-cancerous aneuploidy, we propose that cancer is the phenotype of cells above a certain threshold of aneuploidy. This threshold is reached either by the gradual, stepwise increase in the level of aneuploidy as a consequence of the autocatalysed genetic instability of aneuploid cells or by tetraploidization followed by a gradual loss of chromosomes. Thus the initiation step of carcinogenesis produces aneuploidy below the threshold for cancer, and the promotion step increases the level of aneuploidy above this threshold. We conclude that aneuploidy offers a simple and coherent explanation for all the cancer-specific phenotypes. Accordingly, the gross biochemical abnormalities, abnormal cellular size and morphology, the appearance of tumour-associated antigens, the high levels of secreted proteins responsible for invasiveness and loss of contact inhibition, and even the daunting genetic instability that enables cancer cells to evade chemotherapy, are all the natural consequence of the massive over- and under-expression of proteins.