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AQP5揭示了胃干细胞和胃癌起源
作者:小柯机器人 发布时间:2020/2/10 9:55:37

新加坡科技研究局Nick Barker研究组的最新研究发现AQP5丰富了对远端胃中的干细胞和胃癌起源的认知。2020年2月5日,国际学术期刊《自然》在线发表了这一成果。

研究人员通过沿小鼠胃肠道LGR5 +干细胞群体的比较分析鉴定,并在功能上验证膜蛋白AQP5可作为小鼠和人类成年幽门干细胞的标志物。研究人员利用新生的Aqp5-creERT2小鼠模型发现,AQP5 +隔室内的干细胞是WNT驱动的体内侵入性胃癌细胞的来源。此外,肿瘤驻留的AQP5 +细胞可以在体外选择性启动类器官生长,这表明该种细胞包含潜在的癌症干细胞。在人类中,AQP5主要在肠道和弥漫性亚型的胃癌中(以及在这些亚型的转移中)表达,并且与健康组织相比,常表现出细胞定位的改变。这些新近鉴定出的标记物和小鼠模型将为破译胃癌早期形成以及人胃干细胞的分离和表征提供宝贵资源,这也为临床上利用这些细胞进行再生医学提供了可能。

据介绍,LGR5标记了小鼠幽门胃腺体基部的成年上皮干细胞,但是由于缺乏可用于其分离和验证的表面标记物,因此其等效的人类干细胞群体仍然未知。在肠道癌的小鼠模型中,WNT途径过度激活后,LGR5 +肠道干细胞是癌症细胞的主要来源。然而,WNT信号通路失调后幽门LGR5 +干细胞对胃癌进展的作用是未知的(这是人类胃癌中的常见事件)。

附:英文原文

Title: AQP5 enriches for stem cells and cancer origins in the distal stomach

Author: Si Hui Tan, Yada Swathi, Shawna Tan, Jasmine Goh, Ryo Seishima, Kazuhiro Murakami, Masanobu Oshima, Toshikatsu Tsuji, Phyllis Phuah, Liang Thing Tan, Esther Wong, Aliya Fatehullah, Taotao Sheng, Shamaine Wei Ting Ho, Heike I. Grabsch, Supriya Srivastava, Ming Teh, Simon L. I. J. Denil, Seri Mustafah, Patrick Tan, Asim Shabbir, Jimmy So, Khay Guan Yeoh, Nick Barker

Issue&Volume: 2020-02-05

Abstract:LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach1, but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5+ intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway2. However, the contribution of pyloric LGR5+ stem cells to gastric cancer following dysregulation of the WNT pathway—a frequent event in gastric cancer in humans3—is unknown. Here we use comparative profiling of LGR5+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5+ compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5+ cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.

DOI: 10.1038/s41586-020-1973-x

Source: https://www.nature.com/articles/s41586-020-1973-x

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html