在小鼠模型中，Cd44阳性胃细胞中的E-钙粘蛋白损失引发弥漫性癌症
E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.
摘要(中文译文)
CDH1在散发性弥漫型胃癌（DGC）中常发生突变，而种系CDH1突变是大多数遗传性弥漫型胃癌（HDGC）癌症综合征病例的基础。我们旨在通过在小鼠胃中失活CDH1来建立散发性DGC和遗传性DGC的小鼠模型。我们利用CDH1启动子驱动、携带tdTomato报告基因的他莫昔芬诱导型Cre/loxP系统，构建了DGC小鼠模型。共开发了两种模型：一种为单独敲除CDH1（CDH1-Cre/Cdh1fl/fl），另一种为联合敲除CDH1和Trp53的更具侵袭性模型（CDH1-Cre/Cdh1fl/fl/Trp53fl/fl）。单独失活CDH1可在诱导后1周内导致胃内出现多灶性原位（pTis）印戒细胞（SRC），并在2个月内发展为黏膜内DGC（pT1a期）。至9个月时，50%的小鼠已发展为晚期（pT3）DGC。大多数胃腺癌的形态与人类DGC相似，表现为黏附力差的印戒细胞和低分化细胞。额外敲除Trp53可加速癌症发展，在3个月内即可导致pT3期DGC。此后，Trp53小鼠频繁发生胸腺淋巴瘤和软组织肉瘤。DNA测序未发现两种模型中存在癌症进展所必需的其他遗传事件的证据。来源于Cdh1和Cdh1/Trp53小鼠的类器官表现出形态紊乱，印戒细胞移位至上皮平面之外。观察到与细胞间黏附、肌动蛋白细胞骨架相互作用及NF-κB信号传导等过程相关的转录改变。在表达CDH1的细胞中单独失活CDH1即足以在小鼠中诱导DGC。同时失活Trp53可显著加速肿瘤生长。
Abstract
is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline mutations underlie most cases of the cancer syndrome hereditary DGC. We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of in the mouse stomach. We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the promoter with a tdTomato reporter. Two models were developed, one with -knockout alone (-Cre/ ()) and a second more aggressive model with combined and knockout (-Cre/ ()). inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1 week of induction and intramucosal DGC (stage pT1a) within 2 months. By 9 months, 50% of mice had developed advanced (pT3) DGC. The morphology of most gastric carcinomas was comparable to human DGC, exhibiting poorly cohesive SRC and poorly differentiated cells. Additional knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, mice frequently developed thymic lymphomas and soft tissue sarcomas. DNA sequencing did not find evidence of additional genetic events necessary for cancer progression in either model. Organoids derived from and mice showed a disrupted morphology with SRCs displaced out of the epithelial plane. Transcriptional changes associated with processes including cell-to-cell adhesion, interaction with the actin cytoskeleton and NF-κB signalling were observed. Inactivation of alone in -expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent inactivation.
如何引用
AMA
Lyvianne Decourtye-Espiard, Emily Schulpen, Kate McElroy, Amanda Charlton, Rachel S van der Post, Tanis Godwin, et al. E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.. Gut. 2026; doi:10.1136/gutjnl-2025-336182.
APA
Lyvianne Decourtye-Espiard, Emily Schulpen, Kate McElroy, Amanda Charlton, Rachel S van der Post, Tanis Godwin, et al (2026). E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.. Gut. https://doi.org/10.1136/gutjnl-2025-336182
GB/T 7714
Lyvianne Decourtye-Espiard, Emily Schulpen, Kate McElroy, Amanda Charlton, Rachel S van der Post, Tanis Godwin, et al. E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.[J]. Gut, 2026 doi:10.1136/gutjnl-2025-336182.
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