The Role of Globo-Series Glycolipids in Breast Cancer Stem Cells

• Main Authors: Cheung, Ka Chi Sarah, 張嘉慈
• Other Authors: Wong, Chi-Huey
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/71613775522493570529

博士 === 國立清華大學 === 化學系 === 104 === It is proposed that cancer stem cells (CSCs) are special cancer cells responsible for the self-renewal and differentiation in the heterogeneous cancer tissues for supporting tumor hierarchy. There are numerous evidences showing the existence of CSCs in different cancer types. At the same time, CSCs is closely related to cancer progression, as well as the problems in the current cancer therapies such as metastasis and cancer relapse. Therefore, it has stimulated interests in developing new cancer therapies and early diagnosis targeted on CSCs. In order to enrich CSCs for the further studies, many CSC markers were idenified in this decade. However, these marker sets are often not selective enough to enrich such unique cell population. In this research, therefore, using globo-series epitopes, which is associated with embryogenesis and cancers, as the additional marker for enrichment of breast cancer stem cells (BCSCs) were investigated. At the beginning of the research, it was found that globo-series epitopes stage-specific embryonic antigen-3 (SSEA-3), stage-specific embryonic antigen-4 (SSEA-4) and globo-H were significantly expressed in BCSCs identified with marker systems CD44/CD24 and ESA/PROCR. This study was also illustrated that BCSCs isolated with CD44+CD24-/loSSEA-3+ or ESAhiPROCRhiSSEA-3+ markers had higher tumorigenicity than those with conventional markers in vitro and in vivo. As few as 10 cells with CD44+CD24-/loSSEA-3+ formed tumor in mice, compared to more than 100 cells with CD44+CD24-/lo. Suppression of SSEA-3 by knockdown of the gene encoding b-1,3-galactosyltransferase 5 (b3GalT5) in the globo-series pathway induced the changes of surface markers on cancer cells. Additionally, the overexpression of b3GalT5 enhanced the percentage of cells carrying SSEA-3, and CD44+CD24-/lo. This finding was further supported by the analysis of SSEA-3 and the two related globo-series epitopes SSEA4 and globo-H in stem cells (ESCs and iPSCs), normal and cancer cells. In addition of the apoptosis and cell death in knockdown b3GalT5 in cancer culture but not in normal one, this study gives solid evidence on the potential cancer therapy targeting the globo-series glycans and the late-stage clinical trials of a breast cancer vaccine.