4.6 Article

Identification of a SOX2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profile

期刊

NEURO-ONCOLOGY
卷 13, 期 11, 页码 1178-1191

出版社

OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/nor113

关键词

cancer stem cell; glioma; SOX2; subset

资金

  1. Swedish Cancer Society (Cancerfonden)
  2. Swedish Childhood Cancer Foundation (Barncancerfonden)
  3. Swedish Research Council (Vetenskapsradet)
  4. Stockholm Cancer Society (Cancerforeningen i Stockholm)
  5. Karolinska Institutet
  6. Novartis

向作者/读者索取更多资源

Putative cancer stem cells have been identified in glioblastomas and are associated with radio- and chemoresistance. Further knowledge about these cells is thus highly warranted for the development of better glioblastoma therapies. Gene expression analyses of 11 high-grade glioma cultures identified 2 subsets, designated type A and type B cultures. The type A cultures displayed high expression of CXCR4, SOX2, EAAT1, and GFAP and low expression of CNP, PDGFRB, CXCL12, and extracellular matrix proteins. Clinical significance of the 2 types was indicated by the expression of type A-and type B-defining genes in different clinical glioblastoma samples. Classification of glioblastomas with type A- and type B-defining genes generated 2 groups of tumors composed predominantly of the classical, neural, and/or proneural subsets and the mesenchymal subset, respectively. Furthermore, tumors with EGFR mutations were enriched in the group of type A samples. Type A cultures possessed a higher capacity to form xenograft tumors and neurospheres and displayed low or no sensitivity to monotreatment with PDGF-and IGF-1-receptor inhibitors but were efficiently growth inhibited by combination treatment with low doses of these 2 inhibitors. Furthermore, siRNA-induced downregulation of SOX2 reduced sphere formation of type A cultures, decreased expression of type A-defining genes, and conferred sensitivity to monotreatment with PDGF-and IGF-1receptor inhibitors. The present study thus describes a tumor-and neurosphere-forming SOX2-dependent subset of glioblastoma cultures characterized by a gene expression signature similar to that of the recently described classical, proneural, and/or neural subsets of glioblastoma. The findings that resistance to PDGF-and IGF-1-receptor inhibitors is related to SOX2 expression and can be overcome by combination treatment should be considered in ongoing efforts to develop novel stem cell-targeting therapies.

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