The present study was undertaken to assess the role of tumor-associated urokinase-type plasminogen activator (uPA) and its inhibitor type 1 (PAI-1) as a predictor for early relapse and poor prognosis in patients with stage II cervical cancer of the uterus. We have investigated the localization of uPA and PAI-1 immunohistochemically in formalin-fixed paraffin-embedded tissue sections. uPA and PAI-1 were analyzed anti-genically, enzymologically, and zymographically in 28 patients with pelvic lymph node involvement and in 34 cases without nodal spread, as well as in 10 cases with normal cervix. In cancer tissues, strong staining for uPA was found in areas with invasive growth and degradation of surrounding normal tissue, while most tumor nests showed a mild or a moderate, evenly distributed PAI-1 staining. A significantly higher lymph node-positive rate was observed in patients having tumors with strong uPA and/or PAI-1 stainings than in those with tumors with weak stainings. In spite of significantly higher PAI-1 levels in the primary neoplastic tissues, uPA was found to be increased as well, both in antigen level and in activity. Most of PAI-1 obtained from cancer extracts is the latent form. These results suggest that cancer-associated increase in uPA seems not to be affected (or inhibited) by PAI-1 in areas where tumor cells are invading normal tissue. The overall survival and progression-free survival rate was worst in patients with the strong uPA staining confined to the tumor stromas and also with the strong PAI-1 staining at tumor nests, indicating that the greater localization of uPA in stromal cells than in malignant cells is a predictor of early relapse and poor prognosis in patients with cervical cancer of the uterus. Thus, the staining intensities and the localization of uPA and PAI-1 in tissue specimens appear to be predictors of increasing risk for lymph node metastasis, suggesting that some tumor cells recruit stromal cells to produce uPA and that PAI-1 may not act as a defense mechanism for tumor cell invasion and metastasis in the leading edge of tumor growth.

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