Invasion into brain parenchyma is an inherent feature of the malignant phenotype of glial neoplasms. The list of candidate invasion genes includes integrins, matrix remodeling enzymes (proteases), and other mediators of cell motility such as SPARC and BEHAB, which are well-characterized processes known to support migration or invasion of fetal cells, normal mature cells, as well as tumor cells. While it is anticipated that glioma invasion would exploit some normal genetic, molecular pathology specific to brain invasion transformed as been elucidated. Our success to date with laser capture microdissection of glioma cells from tumor core and invasive rim followed by mRNA differential display leads us to HYPOTHESIZE that local invasion by malignant glioma cells is driven by specific and unique gene expression changes. Interference with the expression of these genes or function of the gene products is likely to specifically target invasive glioma cells, consequently impacting a major source of tumor recurrence. This hypothesis will be tested by pursuing the following specific aims: 1. sustain the discovery of candidate genes expressed or silenced in highly invasive glioma cells compared to noninvading cells in the same tumor. We will use laser capture microdissection to retrieve from cryostat sections of human glioma specimens both invading cells and cells from the tumor core (non invading) and then employ differential display to identify genes uniquely expressed in these populations of cells. 2. test for clinical validation of the these genes in human glioma invasion. Clinical associations between glioma invasion and gene candidates will be tested by LCM collection of glioma cells from tumor core and invasive rim of biopsies, and subsequent quantitative RT-PCR for gene candidates identified from the differential display. And 3. determine the cellular and biochemical mechanisms of action of these genes. Specific inhibition or activation strategies (antibodies, antisense oligonucleotides, transfection of identified genes, and site-directed mutagenesis), and immunolocalization by confocal microscopy, co-immunoprecipitation with receptors and signaling molecules will be used to determine the function of the genes in glioma invasion. An improved understanding of genetic mechanisms underlying malignant glioma invasion will provide a more thorough repertoire of the molecular pathology of both gliomagenesis and glioma progression, as well as identify novel targets for therapeutic intervention.
| Maupin, Kevin A; Sinha, Arkadeep; Eugster, Emily et al. (2010) Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems. PLoS One 5:e13002 |
| Colvin, Joshua; Monine, Michael I; Gutenkunst, Ryan N et al. (2010) RuleMonkey: software for stochastic simulation of rule-based models. BMC Bioinformatics 11:404 |
| Nakada, Mitsutoshi; Anderson, Eric M; Demuth, Tim et al. (2010) The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. Int J Cancer 126:1155-65 |
| Kislin, Kerri L; McDonough, Wendy S; Eschbacher, Jennifer M et al. (2009) NHERF-1: modulator of glioblastoma cell migration and invasion. Neoplasia 11:377-87 |
| Demuth, Tim; Rennert, Jessica L; Hoelzinger, Dominique B et al. (2008) Glioma cells on the run - the migratory transcriptome of 10 human glioma cell lines. BMC Genomics 9:54 |
| Salhia, Bodour; Tran, Nhan L; Chan, Amanda et al. (2008) The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol 173:1828-38 |
| Hoelzinger, Dominique B; Demuth, Tim; Berens, Michael E (2007) Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst 99:1583-93 |
| Nakada, M; Nakada, S; Demuth, T et al. (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64:458-78 |
| Winkles, Jeffrey A; Tran, Nhan L; Brown, Sharron A N et al. (2007) Role of TWEAK and Fn14 in tumor biology. Front Biosci 12:2761-71 |
| Demuth, Tim; Reavie, Linsey B; Rennert, Jessica L et al. (2007) MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival. Mol Cancer Ther 6:1212-22 |
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