BACKGROUND: Human gliomas account for the most common and malignant tumors in the central nervous system (CNS). Despite optimal treatments, survival of patients with high-grade glioblastoma multiforme (GBM) remains poor. Recent coordinated genomic analyses of a large cohort of clinical GBM specimens identified frequent co-alterations of genes in three core pathwaysthe P53, retinoblastoma (RB), and receptor tyrosine kinase (RTK) pathways that are crucial in gliomagenesis. Further multi-institutional efforts have sub-classified GBMs into four clinical relevant subtypes based on their signature genetic lesions. Among them, PDGFRA overexpression is concomitant with a loss of CDKN2A locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of GBMs. To better understand and design therapeutic strategies against gliomas driven by abnormal platelet-derived growth factor (PDGF) signaling, functional studies using human or mouse models are needed.
MAJOR FINDINGS: In order to establish a model that allows us to assess contributions of different signaling pathways to PDGFRα-induced glioma formation, we generated Ink4a/Arf-deficient primary mouse astrocytes (referred to as mAst hereafter) and human glioma cells that overexpress PDGFRα and/or PDGF-A. We found that activation of PDGFRα confers tumorigenicity to Ink4a/Arf-deficient mAst and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF by retroviral transduction suppresses PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SH-2-containing phosphotyrosine phosphatase SHP-2 or Phosphoinositol 3'-Kinase (PI3K) significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. In clinical glioblastoma specimens, PDGFRα and PDGF-A are co-expressed and such co-expression is linked with activation of SHP-2/AKT/mTOR-signaling. Our data thus suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity.
SIGNIFICANCE: We expect these findings will improve our understanding of the formation of the gliomas with PDGFRA and INK4A/ARF aberrations. There were studies that predicted SHP-2/PTPN11 as one of the linker genes in clinical GBMs that interact with multiple commonly altered genes. Our results functionally validate this hypothesis and identify SHP-2 as a converge point of several signaling pathways such as PDGFR, EGFR, PI3K, and mTOR that are frequently deregulated in GBMs. It thus represents a promising target for treatments against this fatal disease.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05062011-164222 |
| Date | 02 June 2011 |
| Creators | Liu, Kun-Wei |
| Contributors | Li, Luyuan, Cheng, Shi-Yuan, Bowser, Robert, Sobol, Robert W., Monga, Satdarshan P.S. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-05062011-164222/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0017 seconds