Sivasubramaniyan Kavitha, Harichandan Abhishek, Schilbach Karin, Mack Andreas F, Bedke Jens, Stenzl Arnulf, Kanz Lothar, Niederfellner Gerhard, Bühring Hans-Jörg
Department of Internal Medicine II, Division of Hematology, Immunology, Oncology, Rheumatology and Pulmonology, University Clinic of Tübingen, Tübingen, Germany.
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.
Glycobiology. 2015 Aug;25(8):902-17. doi: 10.1093/glycob/cwv032. Epub 2015 May 15.
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.
阶段特异性胚胎抗原-4（SSEA-4）是一种糖鞘脂，在某些癌症中过度表达，并与疾病进展有关。然而，关于SSEA-4的功能以及表达SSEA-4的肿瘤细胞的特征知之甚少。我们的研究发现，许多实体瘤细胞系中的一部分细胞表达SSEA-4，而白血病细胞系中则不表达。荧光激活细胞分选技术分选的SSEA-4(+)前列腺癌细胞形成了细胞间接触有限的成纤维细胞样集落，而SSEA-4(-)细胞形成了鹅卵石样上皮集落。只有源自SSEA-4(+)细胞的集落富含多能胚胎干细胞标志物。此外，DU145和HCT-116细胞的SSEA-4(+)部分中，主要的上皮细胞相关标志物Claudin-7、E-钙黏蛋白、ESRP1和GRHL2表达下调。与细胞系类似，SSEA-4(+)原发性前列腺肿瘤细胞也显示上皮细胞相关标志物表达下调。此外，它们还表现出上皮-间质转化以及间质标志物的上调。此外，SSEA-4(+)细胞会自发地从黏附集落中脱离，并形成侵袭伪足样迁移结构，其中SSEA-4、皮层肌动蛋白以及活性pPI3K、pAkt和pSrc富集并共定位。最后，SSEA-4(+)细胞表现出强大的致瘤能力，稳定敲低SSEA-4的合成会导致细胞与不同细胞外基质的黏附减少。总之，我们引入SSEA-4作为一种新型标志物，用于识别肿瘤细胞的异质性侵袭亚群。此外，细胞表面SSEA-4表达的增加与细胞间相互作用的丧失和迁移表型的获得有关，这表明SSEA-4通过影响细胞与细胞外基质的黏附在癌症侵袭中起重要作用。
