Glycolipid GD3 and GD3 synthase are key drivers for glioblastoma stem cells and tumorigenicity

The cancer stem cells (CSCs) of glioblastoma multiforme (GBM), a grade IV astrocytoma, have been enriched by the expressed marker CD133. However, recent studies have shown that CD133⁻ cells also possess tumor-initiating potential. By analysis of gangliosides on various cells, we show that gangliosid...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 20; pp. 5592 - 5597
Main Authors Yeh, Shih-Chi, Wang, Pao-Yuan, Lou, Yi-Wei, Khoo, Kay-Hooi, Hsiao, Michael, Hsu, Tsui-Ling, Wong, Chi-Huey
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 17.05.2016
Subjects
AC133 Antigen - analysis
Animals
Biological Sciences
Brain cancer
Brain Neoplasms - pathology
Cell Line, Tumor
Cytotoxicity
G(M1) Ganglioside - analysis
Gangliosides - analysis
Gangliosides - physiology
Glioblastoma - chemistry
Glioblastoma - etiology
Glioblastoma - pathology
Humans
Mice
Neoplastic Stem Cells - chemistry
Proto-Oncogene Proteins c-met - metabolism
Sialyltransferases - analysis
Sialyltransferases - physiology
Stem cells
Tumors
gangliosides
GBM
cancer stem cells
ST8SIA1
glycosphingolipids
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Summary:The cancer stem cells (CSCs) of glioblastoma multiforme (GBM), a grade IV astrocytoma, have been enriched by the expressed marker CD133. However, recent studies have shown that CD133⁻ cells also possess tumor-initiating potential. By analysis of gangliosides on various cells, we show that ganglioside D3 (GD3) is overexpressed on eight neurospheres and tumor cells; in combination with CD133, the sorted cells exhibit a higher expression of stemness genes and self-renewal potential; and as few as six cells will form neurospheres and 20–30 cells will grow tumor in mice. Furthermore, GD3 synthase (GD3S) is increased in neurospheres and human GBM tissues, but not in normal brain tissues, and suppression of GD3S results in decreased GBM stem cell (GSC)-associated properties. In addition, a GD3 antibody is shown to induce complement-dependent cytotoxicity against cells expressing GD3 and inhibition of GBM tumor growth in vivo. Our results demonstrate that GD3 and GD3S are highly expressed in GSCs, play a key role in glioblastoma tumorigenicity, and are potential therapeutic targets against GBM.
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Reviewers: X.H., Michigan State University; and V.W., University of Konstanz.
Author contributions: S.-C.Y., Y.-W.L., M.H., T.-L.H., and C.-H.W. designed research; S.-C.Y., P.-Y.W., and Y.-W.L. performed research; S.-C.Y., P.-Y.W., Y.-W.L., K.-H.K., and T.-L.H. analyzed data; S.-C.Y., T.-L.H., and C.-H.W. wrote the paper.
Contributed by Chi-Huey Wong, March 30, 2016 (sent for review January 30, 2016; reviewed by Xuefei Huang and Valentin Wittmann)
1S.-C.Y. and P.-Y.W. contributed equally to this work.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1604721113