de Witte J H, Sweep C G, Klijn J G, Grebenschikov N, Peters H A, Look M P, van Tienoven T H, Heuvel J J, Bolt-De Vries J, Benraad T J, Foekens J A
Department of Chemical Endocrinology, University Hospital Nijmegen, The Netherlands.
Br J Cancer. 1999 Apr;80(1-2):286-94. doi: 10.1038/sj.bjc.6690353.
The prognostic value of tissue-type plasminogen activator (tPA) measured in samples derived from 865 patients with primary breast cancer using a recently developed enzyme-linked immunosorbent assay (ELISA) was evaluated. Since the assay could easily be adapted to the assessment of the complex of tPA with its type-1 inhibitor (PAI-1), it was investigated whether the tPA:PAI-1 complex also provides prognostic information. To this end, cytosolic extracts and corresponding detergent extracts of 100,000 g pellets obtained after ultracentrifugation when preparing the cytosolic fractions for routine steroid hormone receptor determination were assayed. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient r(s) = 0.75, P < 0.001 for tPA and r = 0.50, P < 0.001 for tPA:PAI-1 complex). In both Cox univariate and multivariate analysis elevated levels of (total) tPA determined in the pellet extracts, but not in cytosols, were associated with prolonged relapse-free (RFS) and overall survival (OS). In contrast, high levels of the tPA:PAI-1 complex measured in cytosols, but not in the pellet extracts, were associated with a poor RFS and OS. The prognostic information provided by the cytosolic tPA:PAI-1 complex was comparable to that provided by cytosolic (total) PAI-1. Furthermore, the estimated levels of free, uncomplexed tPA and PAI-1, in cytosols and in pellet extracts, were related to patient prognosis in a similar way as the (total) levels of tPA and PAI-1 respectively. Determination of specific forms of components of the plasminogen activation system, i.e. tPA:PAI-1 complex and free, uncomplexed tPA and/or PAI-1, may be considered a useful adjunct to the analyses of the separate components (tPA and/or PAI-1) and provide valuable additional prognostic information with respect to survival of breast cancer patients.
采用最近开发的酶联免疫吸附测定法（ELISA），对865例原发性乳腺癌患者样本中测得的组织型纤溶酶原激活剂（tPA）的预后价值进行了评估。由于该测定法可轻松适用于评估tPA与其1型抑制剂（PAI-1）的复合物，因此研究了tPA:PAI-1复合物是否也能提供预后信息。为此，在制备用于常规类固醇激素受体测定的胞质级分时，对超速离心后获得的100,000g沉淀的胞质提取物和相应的去污剂提取物进行了检测。发现胞质水平与沉淀提取物中测定的水平之间存在统计学显著相关性（Spearman相关系数r(s)=0.75，tPA的P<0.001；r = 0.50，tPA:PAI-1复合物的P<0.001）。在Cox单变量和多变量分析中，沉淀提取物而非胞质溶胶中测得的（总）tPA水平升高与无复发生存期（RFS）延长和总生存期（OS）相关。相反，胞质溶胶而非沉淀提取物中测得的高水平tPA:PAI-1复合物与不良的RFS和OS相关。胞质tPA:PAI-1复合物提供的预后信息与胞质（总）PAI-1提供的预后信息相当。此外，胞质溶胶和沉淀提取物中游离、未复合的tPA和PAI-1的估计水平分别与tPA和PAI-1的（总）水平以相似的方式与患者预后相关。纤溶酶原激活系统成分的特定形式，即tPA:PAI-1复合物以及游离、未复合的tPA和/或PAI-1的测定，可被视为单独成分（tPA和/或PAI-1）分析的有用辅助手段，并能提供有关乳腺癌患者生存的有价值的额外预后信息。
