Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis
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David S. Liu1,2,3, Sanne J.M. Hoefnagel4, Oliver M. Fisher5, Kausilia K. Krishnadath4,6, Karen G. Montgomery1, Rita A. Busuttil1,3,7, Andrew J. Colebatch1, Matthew Read1,2,3, Cuong P. Duong1,2,*, Wayne A. Phillips1,2,3,8,*, Nicholas J. Clemons1,3,*
1Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
2Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
3Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia
4Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands
5Gastroesophageal Cancer Program, St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, 2010, Australia
6Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands
7The University of Melbourne Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, 3010, Australia
8University of Melbourne Department of Surgery, St Vincent's Hospital, Fitzroy, Victoria, 3065, Australia
Nicholas Clemons, email: [email protected]
Wayne Phillips, email: [email protected]
Keywords: metastasis, esophageal cancer, CDH1, E-cadherin, animal models
Received: September 06, 2016 Accepted: October 19, 2016 Published: November 16, 2016
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.
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