Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.
Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.
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DOI：
10.3390/cancers13040808
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发表时间：
2021-02-15
期刊：
影响因子：
5.2
通讯作者：
Schölch S
中科院分区：
文献类型：
--
作者：
Betzler AM;Nanduri LK;Hissa B;Blickensdörfer L;Muders MH;Roy J;Jesinghaus M;Steiger K;Weichert W;Kloor M;Klink B;Schroeder M;Mazzone M;Weitz J;Reissfelder C;Rahbari NN;Schölch S
尽管结直肠癌是最常见的恶性肿瘤之一，但目前还没有可靠地模拟肿瘤生物学和治疗反应的小鼠模型。在本文中，我们描述了一种新型小鼠模型，其中在小鼠中诱导与结直肠癌相关的突变，导致远端结肠形成肿瘤。通过结肠镜检查监测肿瘤，并检查肿瘤的存活和组织学。我们证明该模型可以在临床、组织学和遗传学上密切模拟人类疾病。此外，该模型对经典结直肠癌治疗的反应比其他小鼠模型更真实。 Trp53基因的不同突变对肿瘤细胞的影响表现出显着差异，类似于其他肿瘤疾病的影响。总之，新模型可以在结直肠癌中进行更准确和更具预测性的实验。背景：结直肠癌（CRC）的发展是一个导致基因改变积累的多步骤过程。尽管发病率很高，但目前还没有小鼠模型能够准确地重现这一过程并模拟散发性结直肠癌。我们的目的是开发和表征 Apc/Kras/Trp53 突变型 CRC（CRC 最常见的遗传亚型）的基因工程小鼠模型 (GEMM)。方法：通过节段性腺-cre 病毒感染，在 Apc、Kras 和 Trp53 条件性突变或敲除的小鼠中诱发肿瘤，通过结肠镜检查进行监测，并通过免疫组织化学和新一代测序进行多个水平的表征。结果：该模型在临床、组织学和遗传学上准确地再现了人类结直肠癌发生过程。 Trp53 R172H 热点突变导致转移能力显着增加。 Trp53 改变的影响以及对该模型治疗的反应与人类 CRC 相似。外显子组测序揭示了多个 CRC 相关基因和致癌途径的自发蛋白质修饰改变，从而产生了类似于人类 CRC 的遗传景观。结论：该模型在许多方面真实地模拟了人类 CRC，使人们对 TP53 在 CRC 中的作用有了新的认识，实现了高度预测性的临床前研究，并证明了 GEMM 在当前转化癌症研究和药物开发中的价值。
Although colorectal cancer is among the most frequent malignant tumors, there are currently no mouse models available that reliably mimic both tumor biology as well as treatment response. In this article, we describe a novel mouse model in which mutations relevant to colorectal cancer are induced in mice, leading to tumor formation in the distal colon. The tumors are monitored via colonoscopy, and the survival and the histology of the tumors are examined. We demonstrate that this model can closely model the human disease clinically, histologically and genetically. In addition, the response of this model to classical colorectal cancer treatments is more realistic than that of other mouse models. The effects of different mutations in the Trp53 gene on tumor cells show striking differences, similar to the effects in other tumor diseases. In summary, the new model allows more accurate and predictive experiments in colorectal cancer. Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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影响因子：
4.5
作者：
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影响因子：
11.1
作者：
Deschoemaeker S;Di Conza G;Lilla S;Martín-Pérez R;Mennerich D;Boon L;Hendrikx S;Maddocks OD;Marx C;Radhakrishnan P;Prenen H;Schneider M;Myllyharju J;Kietzmann T;Vousden KH;Zanivan S;Mazzone M
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You, Ming
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通讯作者：
Huber PE
影响因子：
14.8
作者：
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通讯作者：
Lempicki, Richard A.