Journal Article

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

Pietsch, J M, Panagiotidou, P, Stoecklein, N H, Lindenlauf, N, Driemel, C, Vay, C, Kremling, H, Will, D, Harréus, U, Hoya, V, Gires, O, Vallböhmer, D, Wolters, J, Mack, B, Baldus, S A, Schumacher, S, Raba, K, Knoefel, W T

2014

Overview

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 EpCAM high phenotypes correlate with proliferative stages, whereas EpCAM low/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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420/755 / 692/699/67/1504/1477 / Aged / Animals / Antigens, Neoplasm - genetics / Antigens, Neoplasm - metabolism / Apoptosis / Bone marrow / Bone tumors / Cell adhesion & migration / Cell adhesion molecules / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - metabolism / Cell Biology / Cell Line, Tumor / Cell migration / Cell Movement / Cell Proliferation / Cell surface / Cellular control mechanisms / Development and progression / Epithelial Cell Adhesion Molecule / Epithelial cells / Epithelial-Mesenchymal Transition / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - metabolism / Esophageal Neoplasms - pathology / Esophagus / Gene Expression Regulation, Neoplastic / Genetic aspects / Heterografts / Human Genetics / Humans / Internal Medicine / Lymph nodes / Lymphatic Metastasis - genetics / Lymphatic Metastasis - pathology / Male / Medicine / Medicine & Public Health / Mesenchyme / Metastases / Metastasis / Mice / Mice, Inbred NOD / Middle Aged / Neoplastic Cells, Circulating - metabolism / Neoplastic Cells, Circulating - pathology / Oncology / original-article / Phenotype / Phenotypes / Properties / Protein expression / Transforming Growth Factor beta - metabolism / Tumor cells / Tumors / Xenografts