title: Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis.
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.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Venkata Lokesh
authors.initials: VL
authors.lastname: Battula
authors.forename: Yuexi
authors.initials: Y
authors.lastname: Shi
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Evans
authors.forename: Rui-Yu
authors.initials: RY
authors.lastname: Wang
authors.forename: Erika L
authors.initials: EL
authors.lastname: Spaeth
authors.forename: Rodrigo O
authors.initials: RO
authors.lastname: Jacamo
authors.forename: Rudy
authors.initials: R
authors.lastname: Guerra
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Frank C
authors.initials: FC
authors.lastname: Marini
authors.forename: Gabriel
authors.initials: G
authors.lastname: Hortobagyi
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005732:Gangliosides / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D012799:Sialyltransferases / Q000096:biosynthesis / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; D005732:Gangliosides; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; C019403:ganglioside, GD2; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase