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Context-dependent adaption of EpCAM expression in early systemic esophageal cancer

Oncogene volume 33, pages 4904–4915 (2014)Cite this article

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Abstract

The role of the epithelial cell adhesion molecule EpCAM in cancer progression remains largely unclear. High expression of EpCAM in primary tumors is often associated with more aggressive phenotypes and EpCAM is the prime epithelial antigen in use to isolate circulating tumor cells (CTCs) and characterize disseminated tumor cells (DTCs). However, reduced expression of EpCAM was associated with epithelial-to-mesenchymal transition (EMT) and reports on a lack of EpCAM on CTCs emerged. These contradictory observations might reflect a context-dependent adaption of EpCAM expression during metastatic progression. To test this, EpCAM expression was monitored in esophageal cancer at different sites of early systemic disease. Although most of the primary esophageal tumors expressed high levels of EpCAM, the majority of DTCs in bone marrow lacked EpCAM. In vitro, downregulation of EpCAM expression at the plasma membrane was observed in migrating and invading cells, and was associated with a partial loss of the epithelial phenotype and with significantly decreased proliferation. Accordingly, induction of EMT through the action of TGFβ resulted in substantial loss of EpCAM cell surface expression on esophageal cancer cells. Knock-down or natural loss of EpCAM recapitulated these effects as it reduced proliferation while enhancing migration and invasion of cancer cells. Importantly, expression of EpCAM on DTCs was significantly associated with the occurrence of lymph node metastases and with significantly decreased overall survival of esophageal cancer patients. We validated this observation by showing that high expression of EpCAM promoted tumor outgrowth after xenotransplantation of esophageal carcinoma cells. The present data disclose a dynamic expression of EpCAM throughout tumor progression, where EpCAMhigh phenotypes correlate with proliferative stages, whereas EpCAMlow/negative phenotypes associated with migration, invasion and dissemination. Thus, differing expression levels of EpCAM must be taken into consideration for therapeutic approaches and during clinical retrieval of disseminated tumor cells.

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Acknowledgements

This project was funded by The Wilhelm-Sander-Stiftung (2009.083.1), in part by the Deutsche Forschungsgemeinschaft (DFG STO464/2-2), the Rudolf-Bartling Stiftung (II/89). We thank Christof Seifarth for excellent technical support.

Author contributions

CD and HK performed and analyzed experiments related to EpCAM in vitro and in xenotransplantations. JW, NL and SAB performed and analyzed experiments in primary tumors. SS and DW performed and analyzed experiments on DTCs. KR, CV and SB contributed to experiments, DV, UH, SAB and WTK provided clinical material and clinical data analysis related to EpCAM in primary tumors and in DTCs in patients. PP contributed to EpCAM in vitro experiments. VH and JP contributed to xenotransplantation experiments. NHS and OG designed the experiments, analyzed the data and wrote the manuscript.

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Author notes

  1. C Driemel and H Kremling: The authors contributed equally to this work and are listed in alphabetical order.

  2. N H Stoecklein and O Gires: Both authors equally contributed.

Authors and Affiliations

  1. Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    C Driemel, S Schumacher, J Wolters, N Lindenlauf, V Hoya, J M Pietsch, P Panagiotidou, C Vay, D Vallböhmer, W T Knoefel & N H Stoecklein

  2. Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians University of Munich, Munich, Germany

    H Kremling, D Will, B Mack, U Harréus & O Gires

  3. Institute for Pathology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    S A Baldus

  4. Institute for Transplantation Diagnostics and Cellular Therapy, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    K Raba

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  1. C Driemel
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Correspondence to O Gires.

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Driemel, C., Kremling, H., Schumacher, S. et al. Context-dependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene 33, 4904–4915 (2014). https://doi.org/10.1038/onc.2013.441

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