Betzler Alexander M, Nanduri Lahiri K, Hissa Barbara, Blickensdörfer Linda, Muders Michael H, Roy Janine, Jesinghaus Moritz, Steiger Katja, Weichert Wilko, Kloor Matthias, Klink Barbara, Schroeder Michael, Mazzone Massimiliano, Weitz Jürgen, Reissfelder Christoph, Rahbari Nuh N, Schölch Sebastian
Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Cancers (Basel). 2021 Feb 15;13(4):808. doi: 10.3390/cancers13040808.
Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC.
Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.
The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.
This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.
结直肠癌（CRC）的发生是一个多步骤过程，会导致基因改变的积累。尽管其发病率很高，但目前尚无能够准确重现这一过程并模拟散发性CRC的小鼠模型。我们旨在开发并表征一种Apc/Kras/Trp53突变型CRC的基因工程小鼠模型（GEMM），这是CRC最常见的基因亚型。
通过节段性腺病毒-cre病毒感染在Apc、Kras和Trp53具有条件性突变或敲除的小鼠中诱导肿瘤，通过结肠镜检查进行监测，并通过免疫组织化学和下一代测序在多个水平上进行表征。
该模型在临床、组织学和遗传学上准确重现了人类结直肠癌的发生过程。Trp53 R172H热点突变导致转移能力显著增加。Trp53改变的影响以及该模型对治疗的反应与人类CRC相似。外显子组测序揭示了多个CRC相关基因和致癌途径中的自发蛋白质修饰改变，形成了与人类CRC相似的遗传格局。
该模型在许多方面逼真地模拟了人类CRC，有助于深入了解TP53在CRC中的作用，能够进行高度预测性的临床前研究，并证明了GEMMs在当前转化癌症研究和药物开发中的价值。
