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Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis
Venkata Lokesh Battula, … , Sendurai A. Mani, Michael Andreeff
Venkata Lokesh Battula, … , Sendurai A. Mani, Michael Andreeff
Published May 15, 2012
Citation Information: J Clin Invest. 2012;122(6):2066-2078. https://doi.org/10.1172/JCI59735.
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Research Article Oncology Article has an altmetric score of 12

Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis

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Abstract

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 CD44hiCD24lo, 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 CD44hiCD24lo 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.

Authors

Venkata Lokesh Battula, Yuexi Shi, Kurt W. Evans, Rui-Yu Wang, Erika L. Spaeth, Rodrigo O. Jacamo, Rudy Guerra, Aysegul A. Sahin, Frank C. Marini, Gabriel Hortobagyi, Sendurai A. Mani, Michael Andreeff

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Figure 1

GD2 identifies CSCs in breast cancer.

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GD2 identifies CSCs in breast cancer.
(A) HMLER cells were stained with ...
(A) HMLER cells were stained with anti-GD2 antibody by indirect staining and analyzed on an LSR II flow cytometer. GD2+/– gates were drawn based on IgG2a isotype control. FSC, forward scatter. (B) GD2+/– HMLER cells were cell sorted and cultured in cell culture dishes for 4 days. Scale bars: 50 μm. (C) 2 × 104 GD2+/– HMLER cells were cultured in 6-well cell culture dishes in triplicate. Total cells were counted on days 2, 4, and 6 using a Vi-CELL (Beckman Coulter) cell counter. (D) HMLER or MDA-MB-231 cells (1 × 103) were sorted into each well of 24-well ultra-low attachment dishes containing mammosphere growth medium using the FACSAria II cell sorter. Cells were cultured for 12 days, and the photos were taken using a light microscope. Scale bars: 100 μm. (E and F) Number of mammospheres formed from GD2+/– HMLER (E) and MDA-MB-231 (F) cells. The experiment was performed in triplicate. P < 0.01 (G) GD2+/– MDA-MB-231 cells were sorted (1 cell or 5 cells/well) into 96-well ultra-low-attachment dishes containing mammosphere growth medium. Cells were cultured for 12 days, and mammospheres were counted using a light microscope. Scale bars: 200 μm. (H) Number of mammospheres formed from single GD2+/– MDA-MB-231 cells. *P < 0.002. (I) Size of mammospheres measured using a hemocytometer. *P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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