Prognostic significance of uPA and uPAR expression in patients with cervical cancer undergoing radiotherapy

Abstract

Cervical cancer remains a major health threat. Urokinase serves as a marker of metastatic tumors. The present study aimed to determine whether the expression levels of urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR), before and during the course of radiotherapy, serve as prognostic markers for patients with cervical cancer. Cervical tumor tissue biopsies were collected from 72 patients before radiotherapy and after the completion of external beam radiotherapy (EBRT) before intracavitary brachytherapy. The levels of uPA and uPAR were determined using ELISA assays. The significance of the associations between the protein expression levels and the clinical outcomes of patients was determined. Although irradiation enhanced uPA and uPAR expression in cervical cancer cell lines, average uPA levels significantly decreased in tumors, and uPAR levels significantly increased after EBRT. The levels of uPA increased in 12 patients and decreased in 26 patients; and those of uPAR increased in 13 patients and decreased in two patients. Cox regression analysis revealed that increased expression of uPAR was significantly associated with 5-year overall survival rate [hazard ratio (HR), 3.65; 95% confidence interval (CI), 1.18-11.30]. However, the levels of both proteins before radiotherapy failed to predict clinical outcomes. Other significant predictive factors were partial response (HR 7.22; 95% CI 1.17-44.73) and disease progression (HR, 13.41; 95% CI, 1.17-153.07). These findings indicated that increased expression of uPAR in cervical tumor tissue during radiotherapy may serve as a prognostic marker for patients with cervical cancer.

Urokinase-type plasminogen activator receptor (uPAR) assessed by liquid biopsies and PET/CT for prognostication in head and neck cancer patients

“…Regarding treatment stratification, clinicians need a tumor specific pre-treatment biomarker to predict the risk of recurrence. However, in our study pre-treatment total plasma uPAR was not able to predict RFS, in line with the results of previous studies, and a post-treatment sample is irrelevant for selecting therapy 8 . In contrast, we have previously shown that uPAR-PET/CT predicted RFS in a similarly sized study (n = 54) 17 .…”

“…Similarly, an increase in uPAR expression has been documented by other studies, e.g. a study analyzing plasma samples from esophageal cancer patients undergoing radiotherapy and a study on tissue samples collected from p16-positive cervical cancer patients also undergoing radiotherapy 7,8 . In contrast, a small study on HNSCC patients showed a reduction in plasma uPAR (n = 11), but the patients were referred to surgery and the timing of the samples were varying (1-42 days post-treatment) 13 .…”

“…The prognostic value of increasing uPAR levels in blood and tissue samples is well-documented and reflects an imbalance of the urokinase proteolytic system, which results in an overall higher proteolytic activity for the cancer cells to break down the ECM and cause invasion and metastasis [5][6][7][8][9]20 . During radiotherapy treatment our results demonstrated an increase in plasma uPAR.…”

“…uPAR can be shed from the cell surface and the soluble forms of uPAR (suPAR) and cleaved subdomains have been identified in body fluids 3,4 . Several studies have documented the total amount of all uPAR forms to be strong prognostic markers in different types of cancers both in tissue and liquid biopsies [5][6][7][8][9] . Furthermore, increasing uPAR levels during radiotherapy have been associated with poor prognosis in tissue and liquid biopsies 7,8,10 .…”

Compared to preoperative plasma levels post-operative urokinase-type plasminogen activator-1 levels are persistently elevated for 6 weeks after minimally invasive colorectal resection

“…Further, elevated tumor uPA levels have been associated with a worse outcome or more advanced disease for all of these cancers (13)(14)(15)(16)(17)(18)(21)(22)(23). Also, plasma levels of uPA have been shown to be significantly elevated in patients with ovarian, endometrial, non-small cell lung cancer (NSCLC), gastric, hepatocellular, pancreatic, colorectal, and bladder cancers (24)(25)(26)(27)(28).…”