Pathways to Tumorigenesis-Modeling Mutation Acquisition in Stem Cells and Their Progeny
Pathways to Tumorigenesis-Modeling Mutation Acquisition in Stem Cells and Their Progeny
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DOI：
10.1593/neo.08572
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发表时间：
2008-11-01
期刊：
影响因子：
4.8
通讯作者：
Jackson, Trachette L.
中科院分区：
文献类型：
--
作者：
Ashkenazi, Rina;Gentry, Sara N.;Jackson, Trachette L.
大多数成人组织由干细胞、祖细胞和成熟细胞组成，这种分层结构可能在癌变的多步骤过程中起重要作用。在这里，我们发展并讨论了一个简单的数学模型的癌症起始和早期发展的重要预测在一个层次结构的组织。这项工作提出了一个模型，结合了表型改变突变和组织层次的顺序获取。该模型模拟了累积突变导致适应度增加或诱导遗传不稳定的渐进效应。该模型的一个新方面是对称自我更新、不对称分裂和分化都被纳入其中，这使得能够定量研究突变对正常、稳态干细胞分裂模式的影响。该模型还能够预测组织组成和细胞沿着其谱系在任何给定时间和各种突变序列的进展的变化。模拟预测，获得突变的特定顺序对于决定癌症发展的速度至关重要。有趣的是，我们发现遗传稳定性的重要性取决于与干细胞和祖细胞对称自我更新和分化相关的突变的生理表达。特别是，导致干细胞分裂模式改变的突变或在承诺的祖细胞中获得某种程度的不朽，导致癌症的早期发作，并减少遗传不稳定性的影响。
Most adult tissues consist of stem cells, progenitors, and mature cells, and this hierarchical architecture may play an important role in the multistep process of carcinogenesis. Here, we develop and discuss the important predictions of a simple mathematical model of cancer initiation and early progression within a hierarchically structured tissue. This work presents a model that incorporates both the sequential acquisition of phenotype altering mutations and tissue hierarchy. The model simulates the progressive effect of accumulating mutations that lead to an increase in fitness or the induction of genetic instability. A novel aspect of the model is that symmetric self-renewal, asymmetric division, and differentiation are all incorporated, and this enables the quantitative study of the effect of mutations that deregulate the normal, homeostatic stem cell division pattern. The model is also capable of predicting changes in both tissue composition and in the progression of cells along their lineage at any given time and for various sequences of mutations. Simulations predict that the specific order in which mutations are acquired is crucial for determining the pace of cancer development. Interestingly, we find that the importance of genetic stability differs significantly depending on the physiological expression of mutations related to symmetric self-renewal and differentiation of stem and progenitor cells. In particular, mutations that lead to the alteration of the stem cell division pattern or the acquisition of some degree of immortality in committed progenitors lead to an early onset of cancer and diminish the impact of genetic instability.