Ulisse Salvatore, Baldini Enke, Sorrenti Salvatore, D'Armiento Massimino
Department of Experimental Medicine, Section of Endocrinology, Sapienza University of Rome, Rome, Italy.
Curr Cancer Drug Targets. 2009 Feb;9(1):32-71. doi: 10.2174/156800909787314002.
The urokinase plasminogen activator (uPA) system (uPAS) consists of the uPA, its cognate receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2). The uPA converts the proenzyme plasminogen in the serine protease plasmin, involved in a number of physiopathological processes requiring basement membrane (BM) and/or extracellular matrix (ECM) remodelling, including tumor progression and metastasis. Data accumulated over the past years have made increasingly clear that the uPAS has a multifunctional task in the neoplastic evolution, affecting tumor angiogenesis, malignant cell proliferation, adhesion and migration, intravasation and growth at the metastatic site. In agreement with their role in cancer progression and metastasis, an increased expression of uPA, uPAR, and PAI-1 has been documented in several malignant tumors, and a positive correlation between the levels of one or more uPAS members and a poor prognosis has been frequently reported. This is particularly evident in breast cancer, for which uPA has been demonstrated to be the most potent independent prognostic factor described to date. The involvement of the uPAS in cancer progression identifies its components as suitable targets for anti-cancer therapy. Several therapeutical approaches aimed at inhibiting the uPA/uPAR functions have been shown to possess anti-tumor effects in xenograft models, including selective inhibitors of uPA activity, antagonist peptides, monoclonal antibodies able to prevent uPA binding to uPAR and gene therapy techniques silencing uPA/uPAR expression. All these strategies, however, although promising, need definitive confirmation in humans as, up to now, only few uPA inhibitors entered clinical trial.
尿激酶型纤溶酶原激活物（uPA）系统（uPAS）由uPA、其同源受体（uPAR）以及两种特异性抑制剂，即纤溶酶原激活物抑制剂1（PAI-1）和2（PAI-2）组成。uPA将丝氨酸蛋白酶纤溶酶原转化为纤溶酶，参与许多需要基底膜（BM）和/或细胞外基质（ECM）重塑的生理病理过程，包括肿瘤进展和转移。过去几年积累的数据越来越清楚地表明，uPAS在肿瘤演变中具有多功能作用，影响肿瘤血管生成、恶性细胞增殖、黏附与迁移、血管内渗以及转移部位的生长。与其在癌症进展和转移中的作用一致，在几种恶性肿瘤中已记录到uPA、uPAR和PAI-1的表达增加，并且经常报道一种或多种uPAS成员的水平与不良预后之间存在正相关。这在乳腺癌中尤为明显，其中uPA已被证明是迄今为止描述的最有力的独立预后因素。uPAS参与癌症进展确定其成分是抗癌治疗的合适靶点。几种旨在抑制uPA/uPAR功能的治疗方法已在异种移植模型中显示出抗肿瘤作用，包括uPA活性的选择性抑制剂、拮抗肽、能够阻止uPA与uPAR结合的单克隆抗体以及使uPA/uPAR表达沉默的基因治疗技术。然而，所有这些策略虽然很有前景，但在人体中需要明确的证实，因为到目前为止，只有少数uPA抑制剂进入了临床试验。
