Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 6, Pages 2066-2078Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI59735
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Funding
- MD Anderson Research Trust
- NIH [CA-55164, CA-16672, CA116199]
- Paul and Mary Haas Chair in Genetics
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Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have increased resistance to conventional therapies and are capable of establishing metastasis. However, only a few biomarkers of CSCs have been identified. Here, we report that ganglioside GD2 (a glycosphingolipid) identifies a small fraction of cells in human breast cancer cell lines and patient samples that are capable of forming mammospheres and initiating tumors with as few as 10 GD2(+) cells. In addition, the majority of GD2(+) cells are also CD44(hi)CD24(lo), the previously established CSC-associated cell surface phenotype. Gene expression analysis revealed that GD3 synthase (GD3S) is highly expressed in GD2(+) as well as in CD44(hi)CD24(lo) cells and that interference with GD3S expression, either by shRNA or using a pharmacological inhibitor, reduced the CSC population and CSC-associated properties. GD3S knockdown completely abrogated tumor formation in vivo. Also, induction of epithelial-mesenchymal transition (EMT) in transformed human mammary epithelial cells (HMLER cells) dramatically increased GD2 as well as GD3S expression in these cells, suggesting a role of EMT in the origin of GD2(+) breast CSCs. In summary, we identified GD2 as a new CSC-specific cell surface marker and GD3S as a potential therapeutic target for CSCs, with the possibility of improving survival and cure rates in patients with breast cancer.
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