Journal of Neuro-Oncology

, Volume 91, Issue 1, pp 19–26

Signal transduction molecules in gliomas of all grades

  • Ralph P. Ermoian
  • Tania Kaprealian
  • Kathleen R. Lamborn
  • Xiaodong Yang
  • Nannette Jelluma
  • Nils D. Arvold
  • Ruth Zeidman
  • Mitchel S. Berger
  • David Stokoe
  • Daphne A. Haas-Kogan
Laboratory Investigation - Human/Animal Tissue

DOI: 10.1007/s11060-008-9683-5

Cite this article as:
Ermoian, R.P., Kaprealian, T., Lamborn, K.R. et al. J Neurooncol (2009) 91: 19. doi:10.1007/s11060-008-9683-5

Abstract

Purpose To interrogate grade II, III, and IV gliomas and characterize the critical effectors within the PI3-kinase pathway upstream and downstream of mTOR. Experimental design Tissues from 87 patients who were treated at UCSF between 1990 and 2004 were analyzed. Twenty-eight grade II, 17 grade III glioma, 26 grade IV gliomas, and 16 non-tumor brain specimens were analyzed. Protein levels were assessed by immunoblots; RNA levels were determined by polymerase chain reaction amplification. To address the multiple comparisons, first an overall analysis was done comparing the four groups using Spearman’s Correlation Coefficient. Only if this analysis was statistically significant were individual pairwise comparisons done. Results Multiple comparison analyses revealed a significant correlation with grade for all variables examined, except phosphorylated-S6. Expression of phosphorylated-4E-BP1, phosphorylated-PKB/Akt, PTEN, TSC1, and TSC2 correlated with grade (P < 0.01 for all). We extended our analyses to ask whether decreases in TSC proteins levels were due to changes in mRNA levels, or due to changes in post-transcriptional alterations. We found significantly lower levels of TSC1 and TSC2 mRNA in GBMs than in grade II gliomas or non-tumor brain (P < 0.01). Conclusions Expression levels of critical signaling molecules upstream and downstream of mTOR differ between non-tumor brain and gliomas of any grade. The single variable whose expression did not differ between non-tumor brain and gliomas was phosphorylated-S6, suggesting that other protein kinases, in addition to mTOR, contribute significantly to S6 phosphorylation. mTOR provides a rational therapeutic target in gliomas of all grades, and clinical benefit may emerge as mTOR inhibitors are combined with additional agents.

Keywords

Phosphatidylinositol 3-kinase Gliomas Signal transduction mTOR 

Supplementary material

11060_2008_9683_MOESM1_ESM.pdf (711 kb)
MOESM1 [Supplemental Fig. 1 Representative immunoblots used to quantitate expression levels of phosphorylated-S6 and phosphorylated-4E-BP1 (a) and (b). Expression levels were normalized to β-actin levels and then normalized to one another by quantifying and then normalizing the data to control tumor samples.] (PDF 710 kb)

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Ralph P. Ermoian
    • 1
  • Tania Kaprealian
    • 1
  • Kathleen R. Lamborn
    • 2
  • Xiaodong Yang
    • 1
  • Nannette Jelluma
    • 1
  • Nils D. Arvold
    • 1
  • Ruth Zeidman
    • 3
  • Mitchel S. Berger
    • 2
  • David Stokoe
    • 2
    • 3
  • Daphne A. Haas-Kogan
    • 1
    • 2
  1. 1.Department of Radiation OncologyThe University of California, San FranciscoSan FranciscoUSA
  2. 2.Department of Neurosurgery, Brain Tumor Research CenterThe University of California, San FranciscoSan FranciscoUSA
  3. 3.Cancer Research InstituteThe University of California, San FranciscoSan FranciscoUSA

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