Grøndahl-Hansen J, Christensen I J, Rosenquist C, Brünner N, Mouridsen H T, Danø K, Blichert-Toft M
Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
Cancer Res. 1993 Jun 1;53(11):2513-21.
The urokinase pathway of plasminogen activation is supposed to be involved in proteolytic degradation of the extracellular matrix during cancer invasion. The prognostic value of urokinase-type plasminogen activator (uPA) and type 1 plasminogen activator inhibitor (PAI-1) levels in cytosolic extracts of ductal breast carcinomas was studied, retrospectively, in 118 premenopausal and 72 postmenopausal high-risk patients entered into the protocol of Danish Breast Cancer Cooperative Group trials for adjuvant treatment of breast cancer. The median observation time was 8.5 years. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. There is a strong correlation between these levels (P < 0.001; r = 0.57). Univariate analysis showed that a high uPA level is significantly associated with short overall survival in both premenopausal (P < 0.001) and postmenopausal (P = 0.03) patients, while a high PAI-1 content significantly predicts shorter overall survival in premenopausal (P = 0.005) and postmenopausal (P < 0.001) patients and shorter relapse-free survival in postmenopausal patients (P < 0.001). When the levels of uPA and PAI-1 are related to those of other prognostic parameters, both high uPA and high PAI-1 levels are associated with grade of anaplasia in premenopausal patients and with number of tumor-positive lymph nodes in postmenopausal patients. A high PAI-1 level is associated with low estrogen and progesterone receptor levels in both pre- and postmenopausal patients. The prognostic value of uPA and PAI-1 levels was compared with that of established prognostic parameters by multivariate analysis. In premenopausal patients, high uPA is an independent prognostic parameter for shorter overall survival, the relative risk being 2.0 (95% confidence interval, 1.1-3.7). In postmenopausal patients, a high PAI-1 level is a strong and independent factor in predicting shorter overall survival with a relative risk of 2.9 (95% confidence interval, 1.5-5.8). In this group of patients a high PAI-1 level is also an independent predictor of shorter relapse-free survival (relative risk, 2.1; 95% confidence interval, 1.1-3.9). These data together with previous reports indicate that uPA and PAI-1 are potentially important prognostic factors in breast cancer. This is in good agreement with the supposed function of uPA in cancer invasion. It is proposed that PAI-1 plays a role in protecting the tumor against degrading itself. Alternatively, the PAI-1 level may be a biochemical marker of tumor angiogenesis.
纤溶酶原激活的尿激酶途径被认为参与癌症侵袭过程中细胞外基质的蛋白水解降解。对118例绝经前和72例绝经后高危患者进行了回顾性研究，这些患者均参与了丹麦乳腺癌合作组辅助治疗乳腺癌试验方案。他们均为导管乳腺癌患者，研究其细胞溶质提取物中尿激酶型纤溶酶原激活剂（uPA）和1型纤溶酶原激活剂抑制剂（PAI - 1）水平的预后价值。中位观察时间为8.5年。uPA和PAI - 1水平通过夹心酶联免疫吸附测定法测定。这些水平之间存在很强的相关性（P < 0.001；r = 0.57）。单因素分析表明，高uPA水平与绝经前（P < 0.001）和绝经后（P = 0.03）患者的总生存期缩短显著相关，而高PAI - 1含量显著预测绝经前（P = 0.005）和绝经后（P < 0.001）患者的总生存期缩短以及绝经后患者无复发生存期缩短（P < 0.001）。当uPA和PAI - 1水平与其他预后参数相关时，高uPA和高PAI - 1水平在绝经前患者中与间变程度相关，在绝经后患者中与肿瘤阳性淋巴结数量相关。高PAI - 1水平在绝经前和绝经后患者中均与低雌激素和孕激素受体水平相关。通过多因素分析将uPA和PAI - 1水平的预后价值与既定的预后参数进行比较。在绝经前患者中，高uPA是总生存期缩短的独立预后参数，相对风险为2.0（95%置信区间，1.1 - 3.7）。在绝经后患者中，高PAI - 1水平是预测总生存期缩短的强有力独立因素，相对风险为2.9（95%置信区间，1.5 - 5.8）。在该组患者中，高PAI - 1水平也是无复发生存期缩短的独立预测因子（相对风险，2.1；95%置信区间，1.1 - 3.9）。这些数据与先前的报告表明，uPA和PAI - 1是乳腺癌潜在的重要预后因素。这与uPA在癌症侵袭中的假定功能高度一致。有人提出PAI - 1在保护肿瘤免于自身降解中起作用。或者，PAI - 1水平可能是肿瘤血管生成的生化标志物。
