The long term objective of my laboratory is to understand the cellular and molecular mechanisms that underly tumor invasiveness in human gliomas. We have focused on the role of several proteases, their inhibitors and receptors (uPA) that appears to have a direct relationship with the invasive behavior of primary brain tumors, particularly glioblastoma. Recent data has suggested the presence of much higher levels of MMP-9 in glioblastoma samples compared to low- grade gliomas. In the next five years, we plan to focus on the molecular modulation of the expression of these MMP-9 as a basis for the molecular therapy of malignant gliomas. The hypotheses to be tested are; 1) Gene regulation and overexpression of MMP-9 correlate with malignant progression of human gliomas; 2) Modulation of the expression of MMP-9 (with antisense strategy) will provide an inhibitory effect on the invasive behavior of glioblastomas.
The specific Aims are: 1) Determine the invasive capacity of human glioma cell lines in vivo (using nude mice) in relation to 92-kDa type IV collagenase (MMP-9); 2) Determine whether MMP-9 overexpression in cultured glioblastoma cell lines is a consequence of more stable transcript, or elevated gene promoter activity; 3) Determine the effect of an antisense MMP-9 expression vector on the invasive phenotype of cultured glioblastoma cell lines in vitro and in vivo. We believe that determination of the molecular mechanisms that underscore the overexpression of MMP-9 could lead to the development of novel anti-invasive therapeutic agents whose mode of action depends on antagonism of MMP-9 overexpression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056792-06
Application #
2894936
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
1993-08-04
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2001-04-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Lakka, S S; Rajagopal, R; Rajan, M K et al. (2001) Adenovirus-mediated antisense urokinase-type plasminogen activator receptor gene transfer reduces tumor cell invasion and metastasis in non-small cell lung cancer cell lines. Clin Cancer Res 7:1087-93
Tasiou, A; Konduri, S D; Yanamandra, N et al. (2001) A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas. Int J Oncol 19:591-7
Rao, C N; Lakka, S S; Kin, Y et al. (2001) Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. Clin Cancer Res 7:570-6
Kondraganti, S; Mohanam, S; Chintala, S K et al. (2000) Selective suppression of matrix metalloproteinase-9 in human glioblastoma cells by antisense gene transfer impairs glioblastoma cell invasion. Cancer Res 60:6851-5
Lakka, S S; Jasti, S L; Kyritsis, A P et al. (2000) Regulation of MMP-9 (type IV collagenase) production and invasiveness in gliomas by the extracellular signal-regulated kinase and jun amino-terminal kinase signaling cascades. Clin Exp Metastasis 18:245-52
Chintala, S K; Tonn, J C; Rao, J S (1999) Matrix metalloproteinases and their biological function in human gliomas. Int J Dev Neurosci 17:495-502
Uhm, J H; Gladson, C L; Rao, J S (1999) The role of integrins in the malignant phenotype of gliomas. Front Biosci 4:D188-99
Chintala, S K; Kyritsis, A P; Mohan, P M et al. (1999) Altered actin cytoskeleton and inhibition of matrix metalloproteinase expression by vanadate and phenylarsine oxide, inhibitors of phosphotyrosine phosphatases: modulation of migration and invasion of human malignant glioma cells. Mol Carcinog 26:274-85
Mohanam, S; Gladson, C L; Rao, C N et al. (1999) Biological significance of the expression of urokinase-type plasminogen activator receptors (uPARs) in brain tumors. Front Biosci 4:D178-87
Uhm, J H; Dooley, N P; Kyritsis, A P et al. (1999) Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 5:1587-94

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