Prognostic role of urokinase-type plasminogen activator in human gliomas

Abstract

Urokinase-type plasminogen activator (u-PA) is a 54-kd enzyme shown to participate in tissue degradation under certain normal and pathological conditions, including cancer invasion and metastasis. Increased u-PA expression has been found in cancers of the breast, lung, colon, and prostate, and correlated with worse outcome in patients with lung and breast cancer. We examined the correlation between u-PA expression in gliomas and patient survival. Seventy-seven gliomas from 41 men and 36 women (ages 2 to 73) were immunostained for u-PA using monoclonal antibody 394 directed against human urokinase. The tumors included 32 grade 4, 16 grade 3, and 20 grade 2 astrocytomas (Daumas-Duport scale), and 9 pilocytic astrocytomas. Strong cytoplasmic staining was found in tumor cells of all grade 4, most of the grade 3, and a few of the lower grade tumors. Adjacent normal brain tissue showed faint staining associated with subpial cell processes and white matter fibers. The fiber staining was stronger in brain tissue infiltrated by tumor cells. Cytoplasmic u-PA staining in tumor cells was scored from 0 (no staining) to 6 (strong and widespread staining). The mean u-PA scores were 5.08 +/- 0.19 (mean +/- SEM) for grade 4, 3.97 +/- 0.46 for grade 3, 1.65 +/- 0.39 for grade 2, and 1.22 +/- 0.60 for pilocytic astrocytomas. The statistical analysis was based on cytoplasmic staining only. Analysis of variance revealed significant differences between the mean u-PA scores of different grades (P < 0.02 between grades 4 and 3, and P = 0.0001 between grades 4 or 3 and 2, and between grades 4 or 3 and pilocytic), except between grade 2 and pilocytic astrocytomas. Univariate analysis indicated that u-PA score > or = 4 (P = 0.0001), tumor grade 4 (P = 0.01), and age > 50 (P < 0.001) were all significant predictors for shorter disease survival. A three-way interaction model by multivariate analysis indicated that u-PA score > or = 4, tumor grade 4, and age > 50, taken together, were significant factors for shorter patient survival (P < 0.02). We conclude that u-PA may be used as a prognostic tool in conjunction with tumor grade and patients' age in predicting survival for patients with gliomas.