(A)symmetric stem cell replication and cancer.
(A)symmetric stem cell replication and cancer.
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DOI：
10.1371/journal.pcbi.0030053
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发表时间：
2007-03-16
影响因子：
4.3
通讯作者：
Michor F
中科院分区：
文献类型：
--
作者：
Dingli D;Traulsen A;Michor F
后生动物的大多数组织由于细胞死亡或上皮脱落而经历连续的更新。由于细胞复制与诱变的固有风险相关，因此组织由一小群干细胞（SC）维持，这些干细胞缓慢复制以维持其自身群体并产生分化的细胞。越来越多的证据表明，许多肿瘤也是由一小群癌症干细胞维持的，这些干细胞可能是由正常SC突变引起的。SC复制可以是对称的或不对称的。前者可能导致供应链池的扩大。我们描述了一个简单的模型来评估（a）对称SC复制对突变SC扩增的影响，并表明增加不对称复制概率的突变可以导致在没有选择性适应性优势的情况下快速突变SC扩增。几个基因的突变可能导致这一过程，并可能是致癌过程的根源。在多细胞生物中，皮肤、肠道和血液等组织经历连续的细胞更新。这些组织由一小群被称为干细胞（SC）的严格调控的细胞维持，干细胞具有两个定义特性：它们可以自我更新并产生执行组织特定任务的更专门的细胞。体细胞SC存活多年，复制缓慢，以最大限度地降低其DNA突变的风险。当SC分裂时，两个子细胞可能具有相似的特性（对称分裂）或可能具有不同的命运（不对称分裂）。对称分裂可能允许SC扩增，并且改变对称分裂与不对称分裂的概率的突变可能增加肿瘤生长的风险。这种特性很重要，因为越来越多的证据表明，即使是肿瘤也有自己的SC。突变可以将野生型SC转化为具有改变的细胞分裂特性的肿瘤SC，这对癌症进展具有决定性影响。在这里，我们开发了一个数学模型来说明调节SC分裂对称性的突变对肿瘤发展的影响。我们的研究结果提供了新的见解的途径，癌症的突变在SC。
Most tissues in metazoans undergo continuous turnover due to cell death or epithelial shedding. Since cellular replication is associated with an inherent risk of mutagenesis, tissues are maintained by a small group of stem cells (SCs) that replicate slowly to maintain their own population and that give rise to differentiated cells. There is increasing evidence that many tumors are also maintained by a small population of cancer stem cells that may arise by mutations from normal SCs. SC replication can be either symmetric or asymmetric. The former can lead to expansion of the SC pool. We describe a simple model to evaluate the impact of (a)symmetric SC replication on the expansion of mutant SCs and to show that mutations that increase the probability of asymmetric replication can lead to rapid mutant SC expansion in the absence of a selective fitness advantage. Mutations in several genes can lead to this process and may be at the root of the carcinogenic process. In multicellular organisms, tissues such as skin, the gut, and blood undergo continuous cell turnover. These tissues are maintained by a small group of tightly regulated cells known as stem cells (SCs) that have two defining properties: they can renew themselves and give rise to more specialized cells that perform tissue specific tasks. Somatic SCs live for many years and replicate slowly to minimize the risk of acquiring mutations in their DNA. When a SC divides, the two daughter cells may have similar properties (symmetric division) or may have different fates (asymmetric division). Symmetric division may allow SCs to expand, and mutations that alter the probability of symmetric versus asymmetric division might increase the risk of tumor growth. This property is important since there is increasing evidence that even tumors have their own SCs. Mutations can transform wild-type SCs into tumor SCs with modified cell division properties, which have decisive impact on cancer progression. Here we develop a mathematical model to illustrate the impact of mutations that regulate the symmetry of SC division on the development of tumors. Our results provide novel insights on the pathway to cancer by mutations within SCs.