Song Yurong, Gilbert Debra, O'Sullivan T Norene, Yang Chunyu, Pan Wenqi, Fathalizadeh Alisan, Lu Lucy, Haines Diana C, Martin Philip L, Van Dyke Terry
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
PLoS One. 2013 Dec 2;8(12):e80459. doi: 10.1371/journal.pone.0080459. eCollection 2013.
Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages surrounded by a variety of stromal cell types. Understanding cancer etiologies requires evaluating the relationship among cell types during disease initiation and through progression. Genetically engineered mouse (GEM) models facilitate the prospective examination of early oncogenic events, which is not possible in humans. Since most solid tumors harbor aberrations in the RB network, we developed an inducible GEM approach for the establishment and assessment of carcinoma initiation in a diverse range of epithelial tissues and subtypes upon inactivation of RB-mediated tumor suppression (RB-TS). The system allows independent assessment of epithelial subtypes that express either cytokeratins (K) 18 or 19. By Cre-dependent expression of a protein that dominantly inactivates RB and functionally redundant proteins p107 and p130, neoplasia could be initiated in either K18 or K19 expressing cells of numerous tissues. By design, because only a single pathway aberration was engineered, carcinomas developed stochastically only after long latency. Hence, this system, which allows for directed cell type-specific carcinoma initiation, facilitates further definition of events that can progress neoplasms to aggressive cancers via engineered, carcinogen-induced and/or spontaneous evolution.
癌发生于一个复杂的微环境中，该微环境由多种不同的上皮谱系组成，并被多种基质细胞类型所包围。了解癌症病因需要评估疾病起始和进展过程中细胞类型之间的关系。基因工程小鼠（GEM）模型有助于对早期致癌事件进行前瞻性研究，而这在人类中是不可能的。由于大多数实体瘤在RB网络中存在畸变，我们开发了一种可诱导的GEM方法，用于在RB介导的肿瘤抑制（RB-TS）失活后，在多种上皮组织和亚型中建立和评估癌的起始。该系统允许独立评估表达细胞角蛋白（K）18或19的上皮亚型。通过Cre依赖性表达一种能使RB以及功能冗余蛋白p107和p130显性失活的蛋白质，可在多种组织的K18或K19表达细胞中引发肿瘤形成。根据设计，由于仅设计了单一途径畸变，癌仅在长时间潜伏期后随机发生。因此，该系统允许定向的细胞类型特异性癌起始，有助于进一步明确通过工程改造、致癌物诱导和/或自发演变使肿瘤进展为侵袭性癌症的事件。
