文章：

癌症进展动力学

Dynamics of cancer progression

原文发布日期：2004-03-01

DOI: 10.1038/nrc1295

类型: Review Article

开放获取: 否

要点：

1. Cancer is principally caused by mutations in cancer-susceptibility genes, which include oncogenes, tumor-suppressor genes (TSGs) and genes causing genetic instability. Cancer arises when a single cellular lineage receives multiple mutations.
2. Epithelial tissues are subdivided into compartments, and cancer initiation occurs in compartments. Within each compartment, there is a continuous turnover of cells. Each compartment is replenished by division and differentiation of a small number of stem cells. In a healthy tissue, homeostatic mechanisms maintain constant cell numbers.
3. Mathematical models describe the process of cancer initiation and progression and provide a quantitative understanding of the dynamics of tumorigenesis with respect to mutation, selection, genetic instability and tissue architecture.
4. Mutations that activate oncogenes can confer a selective advantage to the cell. We calculate the time until a cellular lineage with an activated oncogene arises and takes over a population of cells.
5. Inactivating both alleles of a TSG also leads to a selective advantage to the cell. The dynamics of TSG inactivation are described by three kinetic laws that depend on the size of the cellular population and the mutation rates. In small, intermediate and large populations, a TSG is inactivated, respectively, by two, one and zero rate-limiting hits.
6. Chromosomal instability (CIN) accelerates the rate of TSG inactivation.
7. It takes two rate-limiting hits to inactivate a TSG in a small population of cells with or without CIN. Therefore, CIN mutations can occur early in tumorigenesis.
8. Knudson's two-hit hypothesis is compatible with the idea that one mutation occurs in the first allele of the TSG and one mutation occurs in a CIN gene. The mutation inactivating the second TSG allele is not rate-limiting in a CIN cell.
9. Because of the tremendous acceleration of loss of heterozygosity in CIN cells, it is very likely that most cancers, which require inactivation of at least two TSGs in rate-limiting scenarios, are initiated by CIN mutations, even if CIN has a severe cost in terms of somatic fitness.

要点翻译：

1. 癌症主要由癌症易感基因的突变引起，这些基因包括癌基因、肿瘤抑制基因（TSG）和导致遗传不稳定的基因。当单个细胞谱系积累多次突变时，癌症便会发生。
2. 上皮组织被划分为不同的区室，癌症的发生始于这些区室。每个区室内存在持续的细胞更新。少量干细胞通过分裂和分化来补充每个区室。在健康组织中，稳态机制维持着恒定的细胞数量。
3. 数学模型描述了癌症发生和进展的过程，并从突变、选择、遗传不稳定性和组织结构的角度，为肿瘤发生的动力学提供了定量理解。
4. 激活癌基因的突变可赋予细胞选择性优势。我们计算了携带激活癌基因的细胞谱系出现并在细胞群体中占据主导地位所需的时间。
5. 使肿瘤抑制基因的两个等位基因均失活同样会赋予细胞选择性优势。TSG失活的动力学由三条动力学定律描述，这些定律取决于细胞群体的大小和突变率。在小型、中型和大型群体中，TSG的失活分别需要两次、一次和零次限速性打击。
6. 染色体不稳定性（CIN）会加速TSG失活的速率。
7. 在小型细胞群体中，无论是否存在CIN，使TSG失活都需要两次限速性打击。因此，CIN突变可能发生在肿瘤发生的早期。
8. 克努森二次打击假说与以下观点相符：一次突变发生在TSG的第一个等位基因上，另一次突变发生在CIN基因上。在CIN细胞中，使第二个TSG等位基因失活的突变并非限速步骤。
9. 由于CIN细胞中杂合性缺失的速度极大加快，即使在体细胞适应性方面CIN代价高昂，大多数需要至少在两种限速情形下使两个TSG失活的癌症，也很可能是由CIN突变启动的。

英文摘要：

Evolutionary concepts such as mutation and selection can be best described when formulated as mathematical equations. Cancer arises as a consequence of somatic evolution. Therefore, a mathematical approach can be used to understand the process of cancer initiation and progression. But what are the fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells? Also, how does a quantitative theory of somatic mutation and selection help us to evaluate the role of genetic instability?

摘要翻译： 

进化概念如突变和选择，在表述为数学方程时能得到最清晰的描述。癌症是体细胞进化的结果，因此可借助数学方法理解其起始与进展。然而，在增殖细胞群体中，激活原癌基因和失活抑癌基因的动态究竟受哪些基本原理支配？定量的体细胞突变与选择理论又如何帮助我们评估遗传不稳定性的作用？

原文链接：

Dynamics of cancer progression