Pretumor progression -: Clonal evolution of human stem cell populations
Pretumor progression -: Clonal evolution of human stem cell populations
复制标题
肿瘤前期进展 人类干细胞群体的克隆进化
DOI：
10.1016/s0002-9440(10)63220-8
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发表时间：
2004-04-01
影响因子：
6
通讯作者：
Shibata, D
中科院分区：
文献类型：
--
作者：
Calabrese, P;Tavaré, S;Shibata, D
通过连续的突变和克隆演替的多步骤癌变通常被描述为肿瘤进展，或肿瘤细胞群的克隆进化。然而，在癌症中发现的许多突变也与正常表型相容，因此遗传进展可能先于肿瘤进展。为了更好地描述这种肿瘤前进展（没有明显表型变化的突变），研究人员建立了一个定量模型，假设大多数致癌癌症突变首先在正常出现的结肠隐窝生态位干细胞中积累。每个隐窝包含多个干细胞，随机的小生境干细胞丢失和替换最终导致所有干细胞谱系的丢失，除了一个。这种生态位继承或隐窝克隆进化类似于肿瘤进展的克隆继承，除了它不需要选择或改变可见表型。在干细胞克隆进化过程中，突变可能通过漂移（客突变）或选择顺序累积。为了确定肿瘤前进展的可行性，突变率足以重建结肠直肠癌的流行病学。癌症的估计。肿瘤前进展可能完全取代可见的肿瘤进展，因为从理论上讲，所有癌症突变都可能首先在正常的结肠中积累，复制保真度正常。升高的突变率或肿瘤发生对于早期进展可能是不必要的。
Multistep carcinogenesis through sequential cycles of mutation and clonal succession is usually described as tumor progression, or the clonal evolution of tumor cell populations. However, many mutations found in cancers are also compatible with normal appearing phenotypes and therefore genetic progression may precede tumor progression. To better characterize such pretumor progression (mutations in the absence of visible phenotypic changes), a quantitative model was developed that postulates most oncogenic cancer mutations first accumulate in normal appearing colon crypt niche stem cells. Each crypt contains multiple stem cells, and random niche stem cell loss with replacement eventually leads to the loss of all stem cell lineages except one. This niche succession or crypt clonal evolution is similar to the clonal succession of tumor progression except it does not require selection or change visible phenotype. Mutations may sequentially accumulate during stem cell clonal evolution either through drift (passenger mutations) or selection. To determine the feasibility of pretumor progression, mutation rates sufficient to recreate the epidemiology of colorectal. cancer were estimated. Pretumor progression may completely substitute for visible tumor progression because it is theoretically possible for all cancer mutations to first accumulate in normal appearing colon with normal replication fidelity. Elevated mutation rates or tumorigenesis may be unnecessary for early progression.