英国威康桑格研究所P. H. Jones小组发现，正常上皮细胞中的突变体克隆能够取代并消除新出现的肿瘤。2021年10月13日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现，大多数新形成的食道肿瘤是通过与邻近正常上皮的突变体克隆竞争而被淘汰的。研究人员在一个食道癌发生的小鼠模型中跟踪了新生的、微小的、恶化前肿瘤的命运，并发现大多数肿瘤迅速消失，没有迹象表明肿瘤细胞死亡、增殖减少或出现抗肿瘤免疫反应。然而，对10天和1年的肿瘤进行深度测序显示了对存活的肿瘤进行选择的证据。在转基因小鼠中诱导高度竞争性的克隆增加了早期肿瘤的清除，而用药物抑制克隆竞争减少了肿瘤的丢失。这些结果支持一个模型：早期肿瘤的生存取决于它们相对于周围正常组织中突变克隆的竞争能力。正常上皮细胞中的突变体克隆在通过细胞竞争清除早期肿瘤方面具有意想不到的抗肿瘤作用，从而保护了组织的完整性。

据介绍，人类上皮组织随着年龄的增长会积累癌症驱动的突变，但肿瘤的形成仍然很罕见。这些突变的正向选择表明，它们改变了增殖细胞的行为和健康状况。因此，正常的成人组织成为一个突变克隆的拼凑体，为空间和生存而竞争，最合适的克隆通过淘汰其竞争力较弱的邻居而扩大。然而，人们对正常上皮细胞中的这种动态竞争如何影响早期肿瘤的发生知之甚少。

附：英文原文

Title: Mutant clones in normal epithelium outcompete and eliminate emerging tumours

Author: Colom, B., Herms, A., Hall, M. W. J., Dentro, S. C., King, C., Sood, R. K., Alcolea, M. P., Piedrafita, G., Fernandez-Antoran, D., Ong, S. H., Fowler, J. C., Mahbubani, K. T., Saeb-Parsy, K., Gerstung, M., Hall, B. A., Jones, P. H.

Issue&Volume: 2021-10-13

Abstract: Human epithelial tissues accumulate cancer-driver mutations with age1,2,3,4,5,6,7,8,9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10,11,12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11,12,13,14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

DOI: 10.1038/s41586-021-03965-7

Source: https://www.nature.com/articles/s41586-021-03965-7