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Expression and Localization of Urokinase-Type Plasminogen Activator in Human Astrocytomas in Vivo¹

Departments of Neurosurgery [M. Y., R. S., S. M., A. K. B., J. S. R.], Pathology [J. M. B.], and Tumor Biology [G. L. N.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Neurosurgery, Fukuoka University School of Medicine, Fukuoka, 814-01, Japan [K. O., M. T.]; and Connective Tissue Research, University of Nebraska Medical Center, Omaha, Nebraska 68198 [V. H. R.]

Plasminogen activators regulate a variety of processes involved in tissue morphogenesis, as well as cell differentiation, migration, and invasion. We examined the relative amounts of mRNA and protein and localization of urokinase-type plasminogen activator (uPA) in human astrocytomas in vivo. Using fibrin zymography and densitometric quantitation, we found that uPA activity was significantly higher in malignant astrocytomas, especially in glioblastomas, than it was in normal brain tissues or low-grade gliomas. The amounts of uPA mRNA, as determined by Northern blot analysis, were higher in anaplastic astrocytomas and glioblastomas than in normal brain tissues and low-grade gliomas, consistent with the amounts of uPA activity. To investigate the cellular source of uPA in various tissues, we performed immunocytochemical localization of uPA protein and in situ hybridization of uPA mRNA with astrocytomas and normal brain tissues. Immunocytochemical staining for uPA showed strong immunoreactivity in the tumor cells and vasculature of glioblastomas and anaplastic astrocytomas but undetectable or very low immunoreactivity for uPA in low-grade gliomas and normal brain tissues. uPA mRNA was located in astrocytoma and endothelial cells and was heterogeneously distributed within glioblastoma, with preferential localization near vascular proliferation and at the leading edge of the tumor. uPA expression was dramatically higher in highly malignant astrocytomas, especially glioblastomas, and was correlated with malignant progression of astrocytomas.

¹ Supported in part by Physicians Referral Service funds from The University of Texas M. D. Anderson Cancer Center, the Wendy Will Case Foundation, and National Cancer Institute Grants CA 56792 (J. S. R.) and CA 44352 (G. L. N.).

² To whom requests for reprints should be addressed, at Department of Neurosurgery, Box 064, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 3/30/94. Accepted 5/26/94.

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