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Zeb2驱动侵袭性和微生物依赖的结肠癌

原文发布日期：2020-06-15

英文摘要：

摘要翻译：

原文链接：

文章：

Zeb2驱动侵袭性和微生物依赖的结肠癌

Zeb2 drives invasive and microbiota-dependent colon carcinoma

原文发布日期：2020-06-15

英文摘要：

Colorectal cancer (CRC) is highly prevalent in Western society, and increasing evidence indicates strong contributions of environmental factors and the intestinal microbiota to CRC initiation, progression and even metastasis. We have identified a synergistic inflammatory tumor-promoting mechanism through which the resident intestinal microbiota boosts invasive CRC development in an epithelial-to-mesenchymal transition-prone tissue environment. Intestinal epithelial cell (IEC)-specific transgenic expression of the epithelial-to-mesenchymal transition regulator Zeb2 in mice (Zeb2IEC-Tg/+) leads to increased intestinal permeability, myeloid cell-driven inflammation and spontaneous invasive CRC development. Zeb2IEC-Tg/+ mice develop a dysplastic colonic epithelium, which progresses to severely inflamed neoplastic lesions while the small intestinal epithelium remains normal. Zeb2IEC-Tg/+ mice are characterized by intestinal dysbiosis, and microbiota depletion with broad-spectrum antibiotics or germ-free rederivation completely prevents cancer development. Zeb2IEC-Tg/+ mice represent the first mouse model of spontaneous microbiota-dependent invasive CRC and will help us to better understand host–microbiome interactions driving CRC development in humans.

摘要翻译：

结直肠癌(Colorectal cancer, CRC)在西方社会中极为常见，越来越多的证据表明环境因素和肠道微生物对 CRC 的发生、进展乃至转移具有显著影响。我们发现了一个协同作用下的炎症肿瘤促进机制：肠道中的居民肠道微生物通过提供一种易发生侵袭性 CRC 发病的上皮至间充质细胞转变易位的易位微环境来促进癌细胞的发展。在小鼠中进行 Zeb2 基因组克隆的 IEC（小肠上皮细胞）特异性转基因表达实验，导致肠道通透性的增加、 myeloid 细胞引发的炎症以及自发性的侵袭性 CRC 发病。这些 Zeb2IEC-Tg/+ 小鼠表现出肠道微生态失衡，并发生从渐进性腺变性到严重炎症性癌前病变的转变；而小肠上皮保持正常状态。Zeb2IEC-Tg/+ 小鼠表现出肠道菌群失调，通过使用广谱抗生素或无菌重编程可完全阻止 CRC 的发展。Zeb2IEC-Tg/+ 小鼠是第一个依赖肠道微生物自行诱导发生的侵袭性 CRC 小鼠模型，这将有助于我们更好地理解宿主-微生物组互动在人类中驱动 CRC 发病的作用机制。