Tetteh Paul W, Kretzschmar Kai, Begthel Harry, van den Born Maaike, Korving Jeroen, Morsink Folkert, Farin Henner, van Es Johan H, Offerhaus G Johan A, Clevers Hans
Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
Department of Pathology, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11859-11864. doi: 10.1073/pnas.1614057113. Epub 2016 Oct 5.
Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1 knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1 KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1 KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.
目前用于结直肠癌的小鼠模型通常与人类结肠癌有显著差异，主要局限于小肠。在此，我们旨在开发一种结肠特异性诱导型小鼠模型，该模型能够忠实地模拟人类结肠癌的起始和进展。碳酸酐酶I（Car1）是一种在结肠上皮细胞中独特表达的基因。我们构建了一种结肠特异性诱导型Car1基因敲入（KI）小鼠，其在近端结肠和盲肠的上皮细胞中具有广泛的Cre活性。利用Car1 KI缺失肿瘤抑制基因Apc会导致盲肠肿瘤形成，但不会在近端结肠产生腺瘤。Apc和Kras同时突变会在盲肠和近端结肠产生微腺瘤，并发展为具有显著发病率的大腺瘤。在联合诱导Apc、Kras、p53和Smad4的致癌突变后，会出现侵袭到淋巴结的侵袭性癌。重要的是，在小肠中未观察到腺瘤。此外，我们观察到来自具有Apc/Kras突变的分化型Car1表达细胞的肿瘤，这表明肠道肿瘤发生的自上而下模型可能发生在多个突变的情况下。我们的结果确立了Car1 KI作为一种有价值的小鼠模型，用于研究结肠特异性肿瘤发生、转移以及癌症起源细胞问题。
