Emerging Clinical Concept: Therapeutic Targeting and Translational Studies of Urokinase in Brain Tumor Invasion
American Association of Colleges of Pharmacy Annual Conference
Objectives: The objective of this study is to investigate the possible interaction between the activation of the Epidermal Growth Factor Receptor and urokinase in promoting brain tumor invasion.
Method: High grade gliomas are aggressive and common brain tumor in adults. Brain tumors account for 2-5% of adult cancer deaths.One of the major pathophysiological features of malignant astrocytomas is their ability to diffusely infiltrate the surrounding brain tissues. Using molecular biology techniques, such as western blot, in vitro invasion assay and mouse in vivo xenograft model, experiments were conducted in triplicate and subjected to statistical analysis using the Student’s t-test and ANOVA with p<0.05.
Results: Our data showed that EGF treatment of glioblastoma cell lines time-dependently up-regulates the expression and activity of urokinase (uPA). The increase in uPA protein by EGF was abrogated by the MEK and tyrosine kinase inhibitors, and siRNA targeting c-Src. Treatment with EGF increased in vitro glioma cell invasion. The increased cell invasion was attenuated by siRNA and shRNA directed against uPA. In addition, uPA knockdown cells decreased in vitro astrocytic tumor invasion and formed small non- invading tumors in mice.
Implications: In summary, we conclude that molecular targeting of urokinase could serve as a therapeutic paradigm in brain tumor invasive growth. We hoped to develop small molecules that target UPA and have the ability to cross the blood brain barrier and so serve as a therapeutic molecule for brain tumor treatment.
Therapy, brain tumor, urokinase, translation
Amos, Samson; Simpson, Denise S.; Ansong, Miriam A.; and Gryka, Rebecca J., "Emerging Clinical Concept: Therapeutic Targeting and Translational Studies of Urokinase in Brain Tumor Invasion" (2014). Pharmacy Practice Faculty Presentations. 681.