Shibata Darryl
Department of Pathology, University of Southern California Keck School of Medicine,
Curr Pathobiol Rep. 2018 Sep;6(3):193-198. doi: 10.1007/s40139-018-0176-8. Epub 2018 Jul 16.
Recent studies demonstrate that normal human tissues accumulate substantial numbers of somatic mutations with aging, to levels comparable to their corresponding cancers. If mutations cause cancer, how do tissues avoid cancer when mutations are unavoidable?
The small intestines (SI) and colon accumulate similar numbers of replication errors, but SI adenocarcinoma is much rarer than colorectal cancer. Both the small and large intestines are subdivided into millions of small neighborhoods (crypts) that are maintained by small numbers of stem cells. To explain the SI cancer paradox, four fundamental evolution parameters (mutation, drift, selection, and population size) are translated to crypts.
The accumulations of driver mutations in a single stem cell may be analogous to an evolutionary poker game. The rarity of SI cancer may reflect that SI crypts are smaller and have fewer stem cells than the colon, which reduces the numbers of cells at risk for mutation and perhaps selection efficiency. Tissue microarchitecture may physically modulate cancer evolution by controlling the numbers of directly competing neighboring cells. A better understanding of the SI cancer paradox may illuminate how tissues naturally avoid cancers when mutations are unavoidable.
近期研究表明，随着年龄增长，正常人体组织会积累大量体细胞突变，其水平与相应癌症相当。如果突变会引发癌症，那么当突变不可避免时，组织是如何避免患癌的呢？
小肠（SI）和结肠积累的复制错误数量相似，但SI腺癌比结直肠癌罕见得多。小肠和大肠都被细分为数百万个由少量干细胞维持的小区域（隐窝）。为了解释SI癌症悖论，将四个基本进化参数（突变、漂变、选择和种群大小）应用于隐窝。
单个干细胞中驱动突变的积累可能类似于一场进化扑克游戏。SI癌症的罕见性可能反映出SI隐窝比结肠更小且干细胞更少，这减少了有突变风险的细胞数量以及可能的选择效率。组织微结构可能通过控制直接竞争的相邻细胞数量来物理调节癌症进化。更好地理解SI癌症悖论可能会阐明当突变不可避免时组织如何自然地避免患癌。
