[论文解读] Cell transformation in tumor-development: a result of accumulation of Misrepairs of DNA through many generations of cells

Jicun Wang-Michelitsch, Thomas M. Michelitsch|arXiv (Cornell University)|May 6, 2015

Science, Research, and Medicine参考文献 13被引用 11

一句话总结

本文提出，肿瘤发生源于多个细胞世代中DNA错误修复的逐步累积，而非单次灾难性事件。它认为，反复的DNA损伤若被错误修复而非正确修复，将导致可遗传的突变在增殖的体细胞中累积，尤其在再生性组织中，通过一种缓慢的、类似衰老的基因组退化过程，驱动细胞转化为癌变表型。

ABSTRACT

Development of a tumor is known to be a result of accumulation of DNA changes in somatic cells. However, the processes of how DNA changes are produced and how they accumulate in somatic cells are not clear. DNA changes include two types: point DNA mutations and chromosome changes. However, point DNA mutations (DNA mutations) are the main type of DNA changes that can remain and accumulate in cells. Severe DNA injuries are the causes for DNA mutations. However, Misrepair of DNA is an essential process for transforming a DNA injury into a survivable and inheritable DNA mutation. In somatic cells, Misrepair of DNA is the main source of DNA mutations. Since the surviving chance of a cell by Misrepair of DNA is low, accumulation of DNA mutations can take place only possibly in the cells that can proliferate. Tumors can only develop in the tissues that are regenerable. The accumulation of Misrepairs of DNA needs to proceed in many generations of cells, and cell transformation from a normal cell into a tumor cell is a slow and long process. However, once a cell is transformed especially when it is malignantly transformed, the deficiency of DNA repair and the rapid cell proliferation will accelerate the accumulation of DNA mutations. The process of accumulation of DNA mutations is actually the process of aging of a genome DNA. Repeated cell injuries and repeated cell regenerations are the two preconditions for tumor-development. For cancer prevention, a moderate and flexible living style is advised.

研究动机与目标

• 阐明DNA突变在 tumorigenesis 过程中如何在体细胞中累积的机制。
• 识别DNA错误修复作为非分裂细胞和增殖细胞中可遗传突变的主要来源。
• 解释为何肿瘤发展缓慢，且仅在细胞更新率高的再生组织中发生。
• 建立一个概念框架，将反复的细胞损伤、组织再生与癌症发生过程中逐步加剧的基因组不稳定性联系起来。

提出的方法

• 对多个细胞世代中DNA损伤与修复动力学进行分析建模。
• 将正确的DNA修复与错误修复事件视为不同的生物学过程。
• 聚焦于点突变，因其具有可遗传性，是持久DNA改变的主要形式。
• 运用“基因组衰老”概念，描述随时间推移错误修复DNA的逐步累积。
• 引入细胞增殖速率和细胞存活概率，以建模突变累积过程。
• 整合关于肿瘤组织中DNA修复缺陷和突变率的实验证据。

实验结果

研究问题

• RQ1 DNA错误修复如何导致体细胞中突变的长期累积？
• RQ2 为何肿瘤发生是一个缓慢的、多代过程，而非急性事件？
• RQ3 反复的细胞损伤与组织再生在突变累积中起什么作用？
• RQ4 为何肿瘤主要在高再生能力的组织中发生？
• RQ5 一旦恶性转化开始，DNA修复缺陷如何加速突变累积？

主要发现

• DNA错误修复是体细胞中可遗传点突变的主要来源，而非直接的DNA损伤。
• 肿瘤发生需要长期的细胞增殖，因为只有分裂细胞才能将错误修复的DNA遗传给后代。
• 错误修复DNA在多个世代中的累积，导致基因组逐渐、类似衰老地退化。
• 肿瘤仅在具有再生能力的组织中发生，因为需要反复的细胞分裂来放大突变。
• 一旦发生恶性转化，缺陷的DNA修复与快速增殖形成正反馈回路，加速突变累积。
• 适度且灵活的生活方式可减少反复的细胞损伤，从而降低突变累积的风险。