Malignant brain tumors represent one of the most refractory cancers to therapy and remain incurable. Gliomas represent the most common type of brain tumors and occur in various grades, with the patients' prognosis inversely proportional to the grade. Therefore, long term objective of his laboratory is to understand the cellular and molecular mechanisms that underly tumor invesiveness in human gliomas. The hypotheses to be tested in this project are: 1) the malignant phenotype and the invasive behavior of the various grades of human gliomas is determined, in part, by the activities of uPA/uPA receptors which in turn relate to the significant prognostic variables/invasiveness. 2) the modulation of the expression of uPA/uPA receptors will provide an inhibitory effect on the invasive behavior of human gliomas.
The Specific Aims are: 1)Determine the invasive capacity of various grades of human glioma biopsy material using an in vitro spheroid model and determine the prognostic markers for the invasiveness of human gliomas in relation to their clinical parameters. They will obtain spheroids from different glioma biopsy material and determine their invasive behavior with fetal rat brain aggregates. They will correlate the intensity of uPA and uPAR in tissue blocks by immunohistochemistry in situ hybridization proportional to their invasiveness in a spheroid model. Finally, the prognostic markers of invasiveness (uPA and uPAR) will be correlated with their clinical parameters (time to progression and survival). 2) Determine the modulation of uPA and uPAR on the invasive phenotype of glioma cells in vitro and in vivo. They will examine the effect of antisense uPA and uPAR expression vector on the invasive phenotype from established glioma cell lines and determine the invasive behavior of these stable transfectants boty in vivo and in vitro. Then they will transfect low-level or deficient uPA and uPAR producing glioma cells with full-length uPA and uPAR and study the invasive behavior of these stable transfectants both in vivo and in vitro. 3) Determine the overexpression of uPA and uPAR in established glioma cells. In this Specific Aim they will determine whether uPA and uPAR overexpression in cultured glioma cell lines is a consequence of the stability of mRNR or of the transcriptional activation of the uPA and uPAR genes. The results of these studies will strengthen their understanding of the role of uPA/uPAR in the biological behavior of the tumors and confirm their significance as prognostic markers. They also believe that determination/modulation of the molecular mechanisms that underscore the over expression of uPA/uPA receptors could lead to the development of novel anti-invasive theraeputic avenues.
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