Kobayashi H, Fujishiro S, Terao T
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Shizuoka, Japan.
Cancer Res. 1994 Dec 15;54(24):6539-48.
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 antigenically, 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.
本研究旨在评估肿瘤相关尿激酶型纤溶酶原激活剂（uPA）及其1型抑制剂（PAI-1）作为II期子宫颈癌患者早期复发和预后不良预测指标的作用。我们采用免疫组织化学方法研究了uPA和PAI-1在福尔马林固定石蜡包埋组织切片中的定位。对28例有盆腔淋巴结受累的患者、34例无淋巴结转移的患者以及10例宫颈正常的患者的组织进行了uPA和PAI-1的抗原性、酶活性及酶谱分析。在癌组织中，uPA在肿瘤浸润生长及周围正常组织降解区域呈强阳性染色，而大多数肿瘤巢PAI-1染色呈轻度或中度且分布均匀。uPA和/或PAI-1染色强的肿瘤患者的淋巴结阳性率显著高于染色弱的患者。尽管原发性肿瘤组织中PAI-1水平显著升高，但uPA在抗原水平和活性方面均有所增加。从癌组织提取物中获得的大部分PAI-1为潜伏形式。这些结果表明，在肿瘤细胞侵袭正常组织的区域，与癌症相关的uPA增加似乎不受PAI-1的影响（或抑制）。uPA染色强且局限于肿瘤基质、同时肿瘤巢PAI-1染色也强的患者的总生存率和无进展生存率最差，这表明uPA在基质细胞中的定位比在恶性细胞中更能预测子宫颈癌患者的早期复发和预后不良。因此，组织标本中uPA和PAI-1的染色强度及定位似乎是淋巴结转移风险增加的预测指标，这表明一些肿瘤细胞招募基质细胞产生uPA，并且PAI-1可能在肿瘤生长前沿的肿瘤细胞侵袭和转移过程中不发挥防御机制的作用。
