CD90 is Identified as a Candidate Marker for Cancer Stem Cells in Primary High-Grade Gliomas Using Tissue Microarrays*

Although CD90 has been identified as a marker for various kinds of stem cells including liver cancer stem cells (CSCs) that are responsible for tumorigenesis, the potential role of CD90 as a marker for CSCs in gliomas has not been characterized. To address the issue, we investigated the expression of CD90 in tissue microarrays containing 15 glioblastoma multiformes (GBMs), 19 WHO grade III astrocytomas, 13 WHO grade II astrocytomas, 3 WHO grade I astrocytomas and 8 normal brain tissues. Immunohistochemical analysis showed that CD90 was expressed at a medium to high level in all tested high-grade gliomas (grade III and GBM) whereas it was barely detectable in low-grade gliomas (grade I and grade II) and normal brains. Double immunofluorescence staining for CD90 and CD133 in GBM tissues revealed that CD133+ CSCs are a subpopulation of CD90+ cells in GBMs in vivo. Flow cytometry analysis of the expression of CD90 and CD133 in GBM-derived stem-like neurospheres further confirmed the conclusion in vitro. The expression levels of both CD90 and CD133 were reduced along with the loss of stem cells after differentiation. Furthermore, the limiting dilution assay demonstrated that the sphere formation ability was comparable between the CD90+/CD133+ and the CD90+/CD133− populations of GBM neurospheres, which is much higher than that of the CD90−/CD133− population. We also performed double staining for CD90 and a vascular endothelial cell marker CD31 in tissue microarrays which revealed that the CD90+ cells were clustered around the tumor vasculatures in high-grade glioma tissues. These findings suggest that CD90 is not only a potential prognostic marker for high-grade gliomas but also a marker for CSCs within gliomas, and it resides within endothelial niche and may also play a critical role in the generation of tumor vasculatures via differentiation into endothelial cells.

[1]  F. DiMeco,et al.  Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. , 2011, Cancer research.

[2]  J. Stamler,et al.  Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2 , 2011, Cell.

[3]  R. McLendon,et al.  Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. , 2011, Cancer cell.

[4]  F. DiMeco,et al.  Glycoproteomic analysis of glioblastoma stem cell differentiation. , 2011, Journal of proteome research.

[5]  Rong Wang,et al.  Glioblastoma stem-like cells give rise to tumour endothelium , 2010, Nature.

[6]  F. DiMeco,et al.  Identification of cell surface glycoprotein markers for glioblastoma-derived stem-like cells using a lectin microarray and LC-MS/MS approach. , 2010, Journal of proteome research.

[7]  H. Ditzel,et al.  Plasma Membrane Proteomics and Its Application in Clinical Cancer Biomarker Discovery* , 2010, Molecular & Cellular Proteomics.

[8]  Guido Nikkhah,et al.  NOTCH Pathway Blockade Depletes CD133‐Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts , 2009, Stem cells.

[9]  R. McLendon,et al.  Targeting Interleukin 6 Signaling Suppresses Glioma Stem Cell Survival and Tumor Growth , 2009, Stem cells.

[10]  Hui Wang,et al.  Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. , 2009, Cancer cell.

[11]  R. McLendon,et al.  Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition , 2008, Stem cells.

[12]  J. Visvader,et al.  Cancer stem cells in solid tumours: accumulating evidence and unresolved questions , 2008, Nature Reviews Cancer.

[13]  Dong-Sup Lee,et al.  Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas , 2008, Laboratory Investigation.

[14]  R. McLendon,et al.  Targeting cancer stem cells through L1CAM suppresses glioma growth. , 2008, Cancer research.

[15]  C. Eberhart,et al.  Medulloblastoma stem cells. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Jian Wang,et al.  CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells , 2008, International journal of cancer.

[17]  S. Fan,et al.  Significance of CD90+ cancer stem cells in human liver cancer. , 2008, Cancer cell.

[18]  A. Olivi,et al.  Cyclopamine‐Mediated Hedgehog Pathway Inhibition Depletes Stem‐Like Cancer Cells in Glioblastoma , 2007, Stem cells.

[19]  J. Dennis,et al.  Clinical‐Scale Expansion of a Mixed Population of Bone Marrow‐Derived Stem and Progenitor Cells for Potential Use in Bone Tissue Regeneration , 2007, Stem cells.

[20]  Qingsong Wang,et al.  Proteomic analysis of a membrane skeleton fraction from human liver. , 2007, Journal of proteome research.

[21]  E. Englund,et al.  CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells. , 2007, Cancer research.

[22]  Alexander Brawanski,et al.  CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. , 2007, Cancer research.

[23]  G. Broggi,et al.  Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells , 2006, Nature.

[24]  Mark W. Dewhirst,et al.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response , 2006, Nature.

[25]  K. Black,et al.  Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma , 2006, Molecular Cancer.

[26]  D. Stearns,et al.  Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. , 2006, Cancer research.

[27]  R. Parks,et al.  Hepatic progenitor cells in human fetal liver express the oval cell marker Thy-1. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[28]  D. Bigner,et al.  Recent advances in the treatment of malignant astrocytoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  J. Giltnane,et al.  Technology Insight: identification of biomarkers with tissue microarray technology , 2004, Nature Clinical Practice Oncology.

[30]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[31]  Paola Pisani,et al.  Genetic Pathways to Glioblastoma , 2004, Cancer Research.

[32]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.

[33]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[34]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[36]  I. Weissman,et al.  Isolation of a candidate human hematopoietic stem-cell population. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[37]  L. Ricci-Vitiani,et al.  Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells , 2011, Nature.