GBM secretome induces transient transformation of human neural precursor cells

Abstract  

Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, with a uniformly poor prognosis. The tumor microenvironment is composed of both supportive cellular substrates and exogenous factors. We hypothesize that exogenous factors secreted by brain tumor initiating cells (BTICs) could predispose normal neural precursor cells (NPCs) to transformation. When NPCs are grown in GBM-conditioned media, and designated as "tumor-conditioned NPCs" (tcNPCs), they become highly proliferative and exhibit increased stem cell self-renewal, or the unique ability of stem cells to asymmetrically generate another stem cell and a daughter cell. tcNPCs also show an increased transcript level of stem cell markers such as CD133 and ALDH and growth factor receptors such as VEGFR1, VEGFR2, EGFR and PDGFRα. Media analysis by ELISA of GBM-conditioned media reveals an elevated secretion of growth factors such as EGF, VEGF and PDGF-AA when compared to normal neural stem cell-conditioned media. We also demonstrate that tcNPCs require prolonged or continuous exposure to the GBM secretome in vitro to retain GBM BTIC characteristics. Our in vivo studies reveal that tcNPCs are unable to form tumors, confirming that irreversible transformation events may require sustained or prolonged presence of the GBM secretome. Analysis of GBM-conditioned media by mass spectrometry reveals the presence of secreted proteins Chitinase-3-like 1 (CHI3L1) and H2A histone family member H2AX. Collectively, our data suggest that GBM-secreted factors are capable of transiently altering normal NPCs, although for retention of the transformed phenotype, sustained or prolonged secretome exposure or additional transformation events are likely necessary.

• Content Type Journal Article
• Category Laboratory Investigation
• Pages 1-10
• DOI 10.1007/s11060-012-0917-1
• Authors
  • Chitra Venugopal, Faculty of Health Sciences, McMaster University Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, MDCL 5027, Hamilton, ON L8S 4K1, Canada
  • X. Simon Wang, Department of Chemistry and Centre for Research in Mass Spectrometry, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada
  • Branavan Manoranjan, Faculty of Health Sciences, McMaster University Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, MDCL 5027, Hamilton, ON L8S 4K1, Canada
  • Nicole McFarlane, Faculty of Health Sciences, McMaster University Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, MDCL 5027, Hamilton, ON L8S 4K1, Canada
  • Sara Nolte, Faculty of Health Sciences, McMaster University Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, MDCL 5027, Hamilton, ON L8S 4K1, Canada
  • Meredith Li, Faculty of Health Sciences, McMaster University Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, MDCL 5027, Hamilton, ON L8S 4K1, Canada
  • Naresh Murty, Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
  • K. W. Michael Siu, Department of Chemistry and Centre for Research in Mass Spectrometry, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada
  • Sheila K. Singh, Faculty of Health Sciences, McMaster University Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, MDCL 5027, Hamilton, ON L8S 4K1, Canada

• Journal Journal of Neuro-Oncology
• Online ISSN 1573-7373
• Print ISSN 0167-594X

http://www.springerlink.com/content/76n543p2475223t1/

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