Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis

• Published in: Oncotarget 2016-12, Vol.7 (50), p.83342-83358
• Main Authors: Liu, David S, Hoefnagel, Sanne J M, Fisher, Oliver M, Krishnadath, Kausilia K, Montgomery, Karen G, Busuttil, Rita A, Colebatch, Andrew J, Read, Matthew, Duong, Cuong P, Phillips, Wayne A, Clemons, Nicholas J
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - secondary; Animals; Apoptosis; Cadherins - genetics; Cadherins - metabolism; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Epithelial-Mesenchymal Transition; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - mortality; Esophageal Neoplasms - pathology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Interleukin Receptor Common gamma Subunit - deficiency; Interleukin Receptor Common gamma Subunit - genetics; Kaplan-Meier Estimate; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - secondary; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Neoplasm Invasiveness; Phenotype; Prognosis; Proportional Hazards Models; Research Paper; RNA Interference; Signal Transduction; Time Factors; Transfection
• ISSN: 1949-2553
• DOI: 10.18632/oncotarget.13391

There is currently a paucity of preclinical models available to study the metastatic process in esophageal cancer. Here we report FLO-1, and its isogenic derivative FLO-1LM, as two spontaneously metastatic cell line models of human esophageal adenocarcinoma. We show that FLO-1 has undergone epithelial-mesenchymal transition and metastasizes following subcutaneous injection in mice. FLO-1LM, derived from a FLO-1 liver metastasis, has markedly enhanced proliferative, clonogenic, anti-apoptotic, invasive, immune-tolerant and metastatic potential. Genome-wide RNAseq profiling revealed a significant enrichment of metastasis-related pathways in FLO-1LM cells. Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1. Consistent with this, repression of E-cadherin expression in FLO-1 cells resulted in increased metastatic activity. Importantly, reduced E-cadherin expression is commonly reported in esophageal adenocarcinoma and independently predicts poor patient survival. Collectively, these findings highlight the biological importance of E-cadherin activity in the pathogenesis of metastatic esophageal adenocarcinoma and validate the utility of FLO-1 parental and FLO-1LM cells as preclinical models of metastasis in this disease.