Ganglioside GD2 Identifies Breast Cancer Stem Cells and Promotes Tumorigenesis

J Clin Invest. 2012 Jun;122(6):2066-78. doi: 10.1172/JCI59735. Epub 2012 May 15.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / biosynthesis*
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CD24 Antigen / genetics
  • CD24 Antigen / metabolism
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gangliosides / biosynthesis*
  • Gangliosides / genetics
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Neoplastic Stem Cells / transplantation
  • Sialyltransferases / biosynthesis
  • Sialyltransferases / genetics
  • Transplantation, Heterologous

Substances

  • Biomarkers, Tumor
  • CD24 Antigen
  • CD24 protein, human
  • Gangliosides
  • Hyaluronan Receptors
  • Neoplasm Proteins
  • ganglioside, GD2
  • Sialyltransferases
  • alpha-N-acetylneuraminate alpha-2,8-sialyltransferase