Abstract
Pleiotrophin (PTN) augments tumor growth by increasing proliferation of tumor cells and promoting vascular abnormalization, but its role in early gliomagenesis has not been evaluated. Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development. To elucidate the role of PTN in tumor initiation we employed the RCAS/tv-a model that allows glioma induction by RCAS-virus mediated expression of oncogenes in neural progenitor cells. Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF)B-induced gliomagenesis. PTN co-treatment augmented PDGFB-induced Akt activation in neural progenitor cells in vitro, and enhanced neural sphere size associated with increased proliferation. Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells.
Keywords:
chromosome 7; glioma; gliomagenesis; pleiotrophin; tumor initiation.
MeSH terms
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Animals
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Avian Proteins / genetics
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Avian Sarcoma Viruses / genetics
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Proliferation / drug effects*
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Cells, Cultured
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Chromosomes, Human, Pair 7
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cytokines / genetics
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Cytokines / metabolism*
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Gene Amplification
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease
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Glioblastoma / genetics
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Humans
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Mice, Transgenic
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Neoplasm Grading
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Neural Stem Cells / drug effects*
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Neural Stem Cells / metabolism
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Neural Stem Cells / pathology
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Phenotype
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-sis / pharmacology*
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Receptors, Virus / genetics
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Signal Transduction / drug effects
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Spheroids, Cellular
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Transfection
Substances
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Avian Proteins
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Carrier Proteins
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Cytokines
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Proto-Oncogene Proteins c-sis
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Receptors, Virus
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Tva receptor
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pleiotrophin
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Proto-Oncogene Proteins c-akt