Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc

Abstract

Summary Strong evidence has accumulated on the prognostic value of tumour-associated proteolytic factors in patients afflicted with solid malignant tumours, including advanced ovarian cancer. We evaluated the prognostic impact of the protease urokinase plasminogen activator (uPA) and its inhibitor PAI-1 on overall survival in patients with advanced ovarian cancer stage FIGO IIIc in order to select patients at risk. uPA and PAI-1 antigen were determined by ELISA in primary tumour tissue extracts of 86 ovarian cancer patients FIGO stage IIIc enrolled in a prospective study. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The time-varying coefficient model of Gray was used to assess the time-dependent strength of prognostic factors tumour mass, uPA and PAI-1 on overall survival. In all patients, uPA and PAI-1 (optimized cut-offs of 2.0 and 27.5 ng mg -1 protein respectively), in addition to the traditional prognostic parameters of residual tumour mass, nodal status, grading and ascites volume, were of prognostic significance in univariate analysis for overall survival. Even in patients with residual tumour mass (n = 43), the statistically independent prognostic impact of PAI-1 persisted, allowing further discrimination between low-and high-risk patients. In multivariate analysis, residual tumour mass (P < 0.001, relative risk (RR) 4.5), PAI-1 (P < 0.001; RR 3.1) and nodal status (P = 0.022, RR 2.6) turned out to be strong, statistically independent prognostic parameters. Evaluation of the time-dependent prognostic impact of residual tumour mass and PAI-1 on overall survival (n = 86, 50 months) revealed that the prognostic power of these factors increased with time. In patients with advanced ovarian cancer, both residual tumour mass and PAI-1 are statistically independent strong prognostic factors. Even within patient subgroups with or without residual tumour mass, PAI-1 allowed selection of patients at risk who might benefit from individualized therapy protocols.

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

“…Based on the experimental end-points that we measured, the decrease in SKOV-3 migration and invasion implies a more favorable scenario to prevent further metastasis. However, since it is well established that increased levels of PAI-1 are associated with a poor prognosis in ovarian cancer [4][5][6][7][8], this apparent contradiction seen here might be better understood by evoking a combination of both traditional and the nontraditional functions of PAI-1. Increased levels of PAI-1, in conjunction with inhibition of the PI3K pathway, would guard the primary tumor mass from host fibrinolytic proteases, effectively decrease localized cell migrationinvasion by inhibition of tumor plasminogen activator capability, promote neovascularization and help to maintain an anti-apoptotic environment in order to allow for genetic changes toward a metastatic phenotype.…”

“…Defining the genetic aberrations and their underlying molecular changes can help in the development of new detection methods and treatments for ovarian cancers. Increased expression of PAI-1 and uPA in ovarian cancers suggests that they are markers linked to a poor prognosis [4][5][6][7][8]. Therefore, it is imperative to understand the regulation of PAI-1 and uPA expression through signal pathways involved in migration and invasion of cancer cells that contribute to the progression and mortality of ovarian cancer.…”

“…Invasive ovarian cancers demonstrate increased levels of the serine protease, urokinase-type plasminogen activator (uPA), and its serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1), compared with benign ovarian cancer or normal ovary. These increased amounts of uPA and PAI-1 are typically correlated with a more aggressive phenotype of ovarian cancer and are linked to a poor prognosis [4][5][6][7][8]. Upon binding its cell surface urokinase receptor (uPAR), uPA activates plasminogen into plasmin to facilitate extracellular matrix degradation and tumor cell invasion.…”

Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer

“…In particular, the last function is thought to be critical in conferring the invasiveness and metastatic potential of cancer cells (Hanahan and Weinberg, 2000). Indeed, this biological role of serine proteases seems to accord well with clinical reports which show that aberrant expression of serine proteases such as the plasminogen activator correlate positively with the invasiveness and metastasis, hence poor prognosis in different malignancies (Monsky et al, 1991;Powell et al, 1993;Herszenyi et al, 1999;Kuhn et al, 1999;Herszenyi et al, 2000).…”

Quantitative analysis of human kallikrein gene 14 expression in breast tumours indicates association with poor prognosis

“…Among the multitude of markers discovered are serine proteases, which participate in many aspects of carcinogenesis, including stimulating cellular growth, angiogenesis and the degradation of the extracellular matrix (Gottesman, 1990;Duffy, 1991). These functions are in accord with clinical studies demonstrating that the aberrant expression of certain serine proteases correlates with the invasiveness and metastasis of cancer cells and predicts poor prognosis in various malignancies (Herszenyi et al, 1999;Kuhn et al, 1999).…”