Foekens John A, Ries Christian, Look Maxime P, Gippner-Steppert Cornelia, Klijn Jan G M, Jochum Marianne
Erasmus MC-Daniel den Hoed, Department of Medical Oncology, 3000 DR Rotterdam, The Netherlands.
Cancer Res. 2003 Jan 15;63(2):337-41.
A variety of serine proteases, including urokinase-type plasminogen activator (uPA), plasmin,and polymorphonuclear leukocyte elastase (PMN-E), have been implicated in the processes of tumor cell invasion and metastasis. Besides degrading of matrix proteins, PMN-E has been shown to be able to cleave and inactivate plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of uPA, and alpha2-antiplasmin, the natural inhibitor of plasmin, thus enabling an uncontrolled matrix degradation by the fibrinolytic enzymes. Because only limited data are available on a relationship between the tumor level of PMN-E and prognosis in primary breast cancer patients, in the present study we have measured with an ELISA the levels of PMN-E (in complex with alpha1-proteinase inhibitor) in cytosolic extracts of 1143 primary breast tumors. Levels of complexed PMN-E have been correlated with the lengths of metastasis-free survival (MFS), relapse-free survival, and overall survival, and a comparison was made with data previously obtained for uPA and PAI-1. Our results show that patients with a high PMN-E level in their primary tumor had a rapid relapse and an early death compared with patients with a low tumor level of PMN-E. This held true for node-negative and node-positive subgroups of patients as well. The relationship of PMN-E with a poor prognosis was especially obvious during short-term follow-up (0-60 months). In Cox multivariate regression analysis, corrected for the traditional prognostic factors, PMN-E was an independent prognostic factor, and high levels of PMN-E were associated with a poor MFS [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.23-2.16; P < 0.001], relapse-free survival (HR, 1.45; 95% CI, 1.10-1.89; P = 0.01), and overall survival (HR, 1.64; 95% CI, 1.20-2.23; P = 0.003). Furthermore, in all three multivariate models, PMN-E still added significantly to the model after the additional inclusion of the uPA. PMN-E was an independent prognostic factor for MFS even in the multivariate analysis including the traditional clinical prognostic factors and the strong established biochemical prognostic factors uPA and PAI-1. Our present study suggests that PMN-E is associated with breast cancer metastasis, and knowledge of the tumor PMN-E status might be helpful in selecting the appropriate individualized (adjuvant) treatment for patients with breast cancer.
多种丝氨酸蛋白酶，包括尿激酶型纤溶酶原激活物（uPA）、纤溶酶和多形核白细胞弹性蛋白酶（PMN-E），都与肿瘤细胞侵袭和转移过程有关。除了降解基质蛋白外，PMN-E还被证明能够切割并使纤溶酶原激活物抑制剂-1（PAI-1，uPA的主要抑制剂）和α2-抗纤溶酶（纤溶酶的天然抑制剂）失活，从而使纤溶酶能够不受控制地降解基质。由于关于原发性乳腺癌患者PMN-E肿瘤水平与预后之间关系的数据有限，在本研究中，我们用酶联免疫吸附测定法（ELISA）测量了1143例原发性乳腺肿瘤细胞提取物中PMN-E（与α1-蛋白酶抑制剂结合）的水平。结合型PMN-E的水平与无转移生存期（MFS）、无复发生存期和总生存期相关，并与先前获得的uPA和PAI-1数据进行了比较。我们的结果表明，与原发性肿瘤中PMN-E水平低的患者相比，原发性肿瘤中PMN-E水平高的患者复发快且死亡早。这在淋巴结阴性和阳性患者亚组中同样成立。在短期随访（0 - 60个月）期间，PMN-E与不良预后的关系尤为明显。在对传统预后因素进行校正的Cox多变量回归分析中，PMN-E是一个独立的预后因素，高水平的PMN-E与不良的MFS相关[风险比（HR），1.63；95%置信区间（CI），1.23 - 2.16；P < 0.001]、无复发生存期（HR，1.45；95% CI，1.10 - 1.89；P = 0.01）和总生存期（HR，1.64；95% CI，1.20 - 2.23；P = 0.003）。此外，在所有三个多变量模型中，在额外纳入uPA后，PMN-E仍然显著增加了模型的预测能力。即使在包括传统临床预后因素以及已确立的强大生化预后因素uPA和PAI-1的多变量分析中，PMN-E仍是MFS的独立预后因素。我们目前的研究表明，PMN-E与乳腺癌转移有关，了解肿瘤PMN-E状态可能有助于为乳腺癌患者选择合适的个体化（辅助）治疗。
