journal contribution
posted on 2023-03-30, 21:05 authored by Joseph D. Dougherty, Elena I. Fomchenko, Afua A. Akuffo, Eric Schmidt, Karim Y. Helmy, Elena Bazzoli, Cameron W. Brennan, Eric C. Holland, Ana Milosevic <p>PDF file - 1.1MB, Histological and immunocytochemical characterization of the RACS-PDGFb-induced tumors in Ntv-a-Olig2-bacTRAP mice resemble human grade IV malignant glioblastoma. A-A1: Low magnification image of the hematoxylin and eosin stained cryostat section of the large, high grade tumor excised from the Ntv-a/ink4a/arf+/- Olig2::EgfpL10a mouse. Higher magnification of the boxed area in A shows similarities with the human GBM, including pseudopalisades (arrows), surrounding areas of necrosis (asterisk), and vascular proliferation (arrowheads). B: Large number of Olig2-positive cells in the PDGF-B-induced glioblastoma on the Ntv-a/ink4a/arf+/- Olig2: EgfpL10a background are labeled with the antibody against proliferation marker Ki67, confirming high proliferative index of tumor cells</p>
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ARTICLE ABSTRACT
Platelet-derived growth factor receptor alpha–positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies. Cancer Res; 72(18); 4856–68. ©2012 AACR.
