生物
肿瘤发生
肿瘤促进
癌症研究
炎症
基因组不稳定性
癌症
免疫系统
免疫学
癌变
遗传学
DNA损伤
DNA
作者
Leslie A. Lange,Eve Kandyba,Kyle Halliwill,Reyno Delrosario,Quân Tran,Nora Bayani,Di Wu,Olga K. Mirzoeva,Melissa Q. Reeves,S. M. Ashiqul Islam,Laura Riva,Erik N. Bergstrom,Kavya Achanta,John DiGiovanni,Ludmil B. Alexandrov,Allan Balmain
标识
DOI:10.1158/2159-8290.cd-24-1379
摘要
Abstract Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. Here, we carried out whole genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues. In the mouse, these cells do not give rise to tumors unless exposed to the tumor promoter TPA. Tissue damage and regenerative proliferation, but not normal cell turnover, consistently trigger tumor formation. Wounding, promoter treatment, and obesity enhance promotion without increasing mutational burden, supporting the possibility of future cancer prevention efforts directed at promotional risk factors.
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