Esophageal Diseases Center and Division of Hematology-Oncology, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA.
Lab Invest. 2020 Jan;100(1):16-26. doi: 10.1038/s41374-019-0278-x. Epub 2019 Jul 10.
Gastroesophageal junction (GEJ) cancer remains a clinically significant disease in Western countries due to its increasing incidence, which mirrors that of esophageal cancer, and poor prognosis. To develop novel and effective approaches for prevention, early detection, and treatment of patients with GEJ cancer, a better understanding of the mechanisms driving pathogenesis and malignant progression of this disease is required. These efforts have been limited by the small number of available cell lines and appropriate preclinical animal models for in vitro and in vivo studies. We have established and characterized a novel GEJ cancer cell line, GEAMP, derived from the malignant pleural effusion of a previously treated GEJ cancer patient. Comprehensive genetic analyses confirmed a clonal relationship between GEAMP cells and the primary tumor. Targeted next-generation sequencing identified 56 nonsynonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer. In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B. Histological examination of subcutaneous flank xenografts in nude and NOD-SCID mice showed a carcinoma with mixed squamous and glandular differentiation, suggesting GEAMP cells contain a subpopulation with multipotent potential. Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro. Thus, GEAMP represents a valuable addition to the limited number of bona fide GEJ cancer cell lines.
胃食管交界处（GEJ）癌症仍然是西方国家具有临床意义的疾病，因为其发病率的增加与食管癌相似，且预后较差。为了开发预防、早期发现和治疗 GEJ 癌症患者的新方法和有效方法，需要更好地了解导致这种疾病发病机制和恶性进展的机制。这些努力受到可用于体外和体内研究的有限数量的可用细胞系和适当的临床前动物模型的限制。我们已经建立并表征了一种新型的 GEJ 癌细胞系 GEAMP，该细胞系源自先前治疗过的 GEJ 癌症患者的恶性胸腔积液。全面的遗传分析证实了 GEAMP 细胞与原发性肿瘤之间的克隆关系。靶向下一代测序在 51 个基因中发现了 56 个非同义改变，包括 TP53 和 APC，这些基因在 GEJ 癌症中经常发生改变。此外，还发现了多个拷贝数改变，包括 EGFR 和 K-RAS 基因扩增以及 CDKN2A 和 CDKN2B 的缺失。裸鼠和 NOD-SCID 小鼠皮下移植瘤的组织学检查显示出一种具有混合鳞状和腺分化的癌，这表明 GEAMP 细胞含有具有多能潜能的亚群。最后，EGFR 信号通路的药理抑制导致关键下游激酶下调和体外细胞增殖抑制。因此，GEAMP 是为数不多的真正 GEJ 癌细胞系的有价值的补充。
