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Glycobiology. 2015 Aug;25(8):902-17. doi: 10.1093/glycob/cwv032. Epub 2015 May 15.

Expression of stage-specific embryonic antigen-4 (SSEA-4) defines spontaneous loss of epithelial phenotype in human solid tumor cells.

Author information

1
Department of Internal Medicine II, Division of Hematology, Immunology, Oncology, Rheumatology and Pulmonology, University Clinic of Tübingen, Tübingen, Germany.
2
Department of Internal Medicine II, Division of Hematology, Immunology, Oncology, Rheumatology and Pulmonology, University Clinic of Tübingen, Tübingen, Germany Department of Urology, University Clinic of Tübingen, Tübingen, Germany.
3
Department of Pediatric Stem Cell Transplantation, University Children's Hospital, Tübingen 72076, Germany.
4
Institute of Clinical Anatomy and Cell Analysis, Eberhard Karls University of Tübingen, Tübingen, Germany.
5
Department of Urology, University Clinic of Tübingen, Tübingen, Germany.
6
Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany.
7
Department of Internal Medicine II, Division of Hematology, Immunology, Oncology, Rheumatology and Pulmonology, University Clinic of Tübingen, Tübingen, Germany hans-joerg.buehring@uni-tuebingen.de.

Abstract

Stage-specific embryonic antigen-4 (SSEA-4) is a glycosphingolipid, which is overexpressed in some cancers and has been linked to disease progression. However, little is known about the functions of SSEA-4 and the characteristics of SSEA-4 expressing tumor cells. Our studies identified SSEA-4 expression on a subpopulation of cells in many solid tumor cell lines but not in leukemic cell lines. Fluorescence-activated cell sorting-sorted SSEA-4(+) prostate cancer cells formed fibroblast-like colonies with limited cell-cell contacts, whereas SSEA-4(-) cells formed cobblestone-like epithelial colonies. Only colonies derived from SSEA-4(+) cells were enriched for pluripotent embryonic stem cell markers. Moreover, major epithelial cell-associated markers Claudin-7, E-cadherin, ESRP1 and GRHL2 were down-regulated in the SSEA-4(+) fraction of DU145 and HCT-116 cells. Similar to cell lines, SSEA-4(+) primary prostate tumor cells also showed down-regulation of epithelial cell-associated markers. In addition, they showed up-regulation of epithelial-to-mesenchymal transition as well as mesenchymal markers. Furthermore, SSEA-4(+) cells escape from adhesive colonies spontaneously and form invadopodia-like migratory structures, in which SSEA-4, cortactin as well as active pPI3K, pAkt and pSrc are enriched and colocalized. Finally, SSEA-4(+) cells displayed strong tumorigenic ability and stable knockdown of SSEA-4 synthesis resulted in decreased cellular adhesion to different extracellular matrices. In conclusion, we introduce SSEA-4 as a novel marker to identify heterogeneous, invasive subpopulations of tumor cells. Moreover, increased cell-surface SSEA-4 expression is associated with the loss of cell-cell interactions and the gain of a migratory phenotype, suggesting an important role of SSEA-4 in cancer invasion by influencing cellular adhesion to the extracellular matrix.

KEYWORDS:

SSEA-4; adhesion; epithelial-to-mesenchymal transition; invadopodia; invasion

PMID:
25978997
PMCID:
PMC4565992
DOI:
10.1093/glycob/cwv032
[Indexed for MEDLINE]
Free PMC Article

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