Grøndahl-Hansen J, Peters H A, van Putten W L, Look M P, Pappot H, Rønne E, Dano K, Klijn J G, Brünner N, Foekens J A
Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Clin Cancer Res. 1995 Oct;1(10):1079-87.
We have recently described the urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) as strong prognostic variables in breast cancer (J. A. Foekens et al., Cancer Res., 52: 6101-6105, 1992; J. Grondahl-Hansen et al., Cancer Res., 53: 2513-2521, 1993; J. A. Foekens et al., J. Clin. Oncol., 11: 899-908, 1994). A specific cell surface receptor (uPAR) binds uPA and strongly enhances plasmin generation, and the amount of uPAR in the tumor tissue might therefore be a rate-limiting factor in the extracellular proteolysis involved in tumor invasion. Here, we report on the prognostic value of uPAR in cytosolic (uPARc) and Triton (uPARt) extracts prepared from 505 primary breast tumors. The median observation time was 54 (range: 12-125) months. uPAR levels were determined by a sandwich ELISA. Univariate analysis showed that high uPAR levels (above the median value) were significantly associated with a shorter overall survival, showing a stronger discriminatory effect for uPARc [relative hazard rate (RHR): 1.47; P = 0.012)] as compared with uPARt (RHR, 1.33; P = 0.059), while no statistically significant differences were found for relapse-free survival. Multivariate analysis including all patients showed that when including other biochemical variables (estrogen receptor, progesterone receptor, PS2, cathepsin D, uPA, and PAI-1), the only retained independent variable via backward elimination was PAI-1 for both relapse-free survival and overall survival. When analyzed separately in clinically relevant subgroups, the prognostic value of uPAR was particularly strong in a subgroup of 201 node-positive postmenopausal women, showing considerably shorter overall (RHR: 2.39; P < 0.0001) and relapse free (RHR: 1.91; P = 0.0006) survival for patients with high uPARc content. High uPARt levels were also significantly associated with shorter overall survival in this subgroup of patients (RHR: 1.5; P = 0.047), but not with relapse-free survival (P = 0.64). Multivariate analysis, including the basic model, estrogen and progesterone receptors, PS2, cathepsin D, uPA, PAI-1, uPARc, and uPARt in the subgroup of postmenopausal node-positive patients, showed that only uPARc and PAI-1 were significant independent prognostic parameters, with respect to overall survival, RHRs being 2.72 (P < 0.0001) and 1.81 (P = 0.005), respectively. In multivariate analysis of relapse-free survival, uPARc, PAI-1, and uPA were independent parameters with respective relative relapse rates of 1.91 (P = 0.002) for uPARc, 1.68 (P = 0.02) for PAI-1, and 1.6 (P = 0.03) for uPA. These data lend support to the hypothesis that uPAR is an important molecule in plasmin-mediated extracellular matrix degradation leading to cancer cell dissemination and death of the patient.
我们最近将尿激酶型纤溶酶原激活剂（uPA）及其1型抑制剂（PAI-1）描述为乳腺癌中强有力的预后变量（J. A. 福肯斯等人，《癌症研究》，52: 6101 - 6105，1992；J. 格伦达尔 - 汉森等人，《癌症研究》，53: 2513 - 2521，1993；J. A. 福肯斯等人，《临床肿瘤学杂志》，11: 899 - 908，1994）。一种特异性细胞表面受体（uPAR）可结合uPA并强力增强纤溶酶生成，因此肿瘤组织中uPAR的量可能是肿瘤侵袭所涉及的细胞外蛋白水解的一个限速因素。在此，我们报告从505例原发性乳腺癌制备的胞质（uPARc）和曲拉通（uPARt）提取物中uPAR的预后价值。中位观察时间为54（范围：12 - 125）个月。uPAR水平通过夹心酶联免疫吸附测定法测定。单因素分析显示，高uPAR水平（高于中位数）与较短的总生存期显著相关，与uPARt相比，uPARc显示出更强的区分效应[相对危险率（RHR）：1.47；P = 0.012]，而无病生存期未发现统计学显著差异（uPARt的RHR为1.33；P = 0.059）。对所有患者进行的多因素分析表明，当纳入其他生化变量（雌激素受体、孕激素受体、PS2、组织蛋白酶D、uPA和PAI-1）时，通过向后排除法唯一保留的独立变量在无病生存期和总生存期方面均为PAI-1。当在临床相关亚组中单独分析时，uPAR的预后价值在201例绝经后淋巴结阳性女性亚组中尤为显著，uPARc含量高的患者总生存期（RHR：2.39；P < 0.0001）和无病生存期（RHR：1.91；P = 0.0006）显著缩短。在该患者亚组中，高uPARt水平也与较短的总生存期显著相关（RHR：1.5；P = 0.047），但与无病生存期无关（P = 0.64）。对绝经后淋巴结阳性患者亚组进行的多因素分析，包括基本模型、雌激素和孕激素受体、PS2、组织蛋白酶D、uPA、PAI-1、uPARc和uPARt，结果显示，就总生存期而言，仅uPARc和PAI-1是显著的独立预后参数，RHR分别为2.72（P < 0.0001）和1.81（P = 0.005）。在无病生存期的多因素分析中，uPARc、PAI-1和uPA是独立参数，uPARc的相对复发率为1.91（P = 0.002），PAI-1为1.68（P = 0.02），uPA为1.6（P = 0.03）。这些数据支持了这样一种假说，即uPAR是纤溶酶介导的细胞外基质降解过程中的一个重要分子，该过程导致癌细胞播散和患者死亡。
