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Cancer/Testis Antigen Expression in Human Mesenchymal Stem Cells: Down-regulation of SSX Impairs Cell Migration and Matrix Metalloproteinase 2 Expression

Departments of ¹ Oncology and Pathology, ² Cellular and Molecular Biology, and ³ Laboratory Medicine, Division of Clinical Immunology, Karolinska Institutet, Sweden and ⁴ Center for Allogenic Stem Cell Transplantation, Karolinska University Hospital, Huddinge, Sweden

Requests for reprints: Bertha Brodin, Cellular and Molecular Tumor Pathology, Cancer Centrum Karolinska (R8; 04), Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46-8-5177 52 44; Fax: 46-8-321047; E-mail: bertha.brodin{at}cck.ki.se.

Several families of genes by and large located on the X chromosome encode proteins of unspecified function. Commonly known as cancer/testis (CT) antigens, they are considered, under normal conditions, only to be expressed in cells of the germ line and placenta. CT genes are also often expressed in cancer cells, hence their classification. Here we report that their expression in normal cells is wider spread and can be observed in cells with the potential for self-renewal and pleuripotency, namely, stem cells. Several CT genes and their products, CT antigens, including SSX, NY-ESO-1, and N-RAGE, were expressed in undifferentiated mesenchymal stem cells (MSCs) and down-regulated after osteocyte and adipocyte differentiation. To elucidate the possible overlapping function played by these genes in cancer and stem cells, a comparative analysis of the localization of their proteins was made. In addition, localization relative to other MSC markers was examined. This revealed that SSX localizes in the cytoplasm and overlap occurs in regions where matrix metalloproteinase 2 (MMP2) and vimentin accumulate. Nevertheless, it was found that no protein interactions between these molecules occur. Further investigation revealed that the migration of a melanoma cell line (DFW), which expresses SSX, MMP2, and vimentin, decreases when SSX is down-regulated. This decrease in cell migration was paralleled by a reduction in MMP2 levels. Analogous to this, SSX expression is down-regulated in MSCs after differentiation; concomitantly a reduction in MMP2 levels occurs. In addition, E-cadherin expression increases, mimicking a mesenchymal epithelial transition. These results afford SSX a functional role in normal stem cell migration and suggest a potentially similar function in cancer cell metastases.

Key Words: Cancer/testis antigens • mesenchymal stem cells • SSX • MMP2 • vimentin

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