Prognostic significance of circulating intact and cleaved forms of urokinase plasminogen activator receptor in inoperable chemotherapy treated cholangiocarcinoma patients
Introduction
Surgery is the only curative treatment option in cholangiocarcinoma. Unfortunately most patients are diagnosed with advanced cholangiocarcinomas when curable resection is no longer possible. As a consequence the prognosis is poor with a 5-year survival rate of less than 5% [26]. In 2010, a large randomized trial including unresectable cholangiocarcinoma patients showed that combination chemotherapy prolongs survival [28]. Unfortunately, far from all patients respond to chemotherapy and a major clinical challenge is to identify the patients who will actually benefit from treatment. In order to accomplish this, predictive and prognostic biomarkers are required. Hence, the prognostic significance of several markers in serum from patients with cholangiocarcinomas has been investigated, but no single marker has so far been proven clinical useful [18].
The components of the plasminogen activation system have been demonstrated to be strong prognostic markers in several cancers, when measured in both tumor tissue and in blood [7]. The plasminogen activation system components, the urokinase-type plasminogen activator (uPA) and its receptor (uPAR), are both essential for pericellular proteolysis which is required for tissue remodeling during both normal physiological conditions such as wound healing [17] and initiation of angiogenesis [14], as well as during cancer invasion [8].
uPAR is a three-domain receptor attached to the cell membrane by a glycolipid-anchor located on domain III [22]. Intact uPAR(I–III) can be cleaved by uPA, releasing domain I (uPAR (I)), while leaving uPAR(II–III) on the cell surface. Both of the glycolipid-anchored uPAR forms (uPAR(II–III) and uPAR(I–III)) can be shed from the cell membrane [17], resulting in three soluble uPAR forms (uPAR(I–III) and uPAR(II–III) as well as uPAR(I)) detectable in the blood. The levels of the cleaved forms may reflect the catalytic activity of uPA [11]. Interestingly, the cleaved soluble uPAR forms have been demonstrated to be independent prognostic markers in various types of cancer, such as colorectal [16], [27], lung [3], prostate [2] and ovarian cancer [10].
Currently, no published data exists on the prognostic significance of circulating uPAR forms in cholangiocarcinoma except from our own previously published study with only nine cholangiocarcinoma patients included [25].
In the present study, we explore whether the levels of different uPAR forms in serum measured before and during chemotherapy predict survival in two cohorts of patients with inoperable cholangiocarcinoma treated according to the same treatment guidelines at two different hospitals.
Section snippets
Design
This a retrospective study, performed in accordance with the REMARK-guidelines [6], [19] reporting all items (1–20) on the REMARK checklist.
Training set
Consecutive patients with inoperable cholangiocarcinoma treated at Rigshospitalet, Copenhagen, from February 2004 to February 2011 were identified (n = 108). Follow-up continued until March 2013.
In the entire study period, a single chemotherapy regimen was used exclusively as standard therapy in bile duct cancer. Hence, it was possible to identify all
Patient and baseline characteristics
Of 170 patients registered as receiving chemotherapy, 108 patients had received chemotherapy for inoperable cholangiocarcinoma and had a baseline (i.e. at the start of treatment) serum sample available for analysis (Supplementary Fig. 1). Serum samples collected after two cycles of treatment were available from 59 patients and 48 of these also had a baseline serum sample available. The number of deaths was 102 of the 108 patients. Patients' baseline-characteristics are presented in Table 1.
Discussion
We have tested two hypotheses: 1) pre-therapeutic levels of the different uPAR forms in serum have prognostic significance and 2) a decrease in the levels of any of the uPAR forms after two cycles of chemotherapy is predictive of survival in inoperable cholangiocarcinoma.
We have demonstrated that elevated serum levels at baseline of all three forms of soluble uPAR are predictive of a poor survival in inoperable cholangiocarcinoma patients. In a test set we were able to confirm that uPAR(I–III) +
Conflicts of interest
None of the authors have conflicts of interest to declare.
Author contributions
MG, MS and GHH designed the study.
MG, ML, TT, UL, MS, LHJ and IKL acquired the data presented in this article.
IJC and MG carried out the statistical analysis.
MG analyzed and interpreted data and drafted the manuscript.
MS, GHH, IJC and IKL performed critical revision of the manuscript for important intellectual content.
GHH and MS supervised the study.
All authors read, revised and finally approved the final manuscript.
Funding
MG is funded by the Oncological Research Foundation, Dept. of Oncology, Rigshospitalet, Denmark.
Acknowledgments
The excellent technical assistance of Ruth Petersson is gratefully acknowledged as well as the useful advices from Professor Nils Brünner.
References (28)
- et al.
Urokinase receptor forms in serum from non-small cell lung cancer patients: relation to prognosis
Lung Cancer
(2011) - et al.
Urokinase receptor variants in tissue and body fluids
Adv Clin Chem
(2007) - et al.
Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer
Ann Oncol
(2012) - et al.
Structure–function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins
FEBS Lett
(1994) - et al.
Prognostic and predictive value of intact and cleaved forms of the urokinase plasminogen activator receptor in metastatic prostate cancer
Prostate
(2011) - et al.
The liberated domain I of urokinase plasminogen activator receptor — a new tumour marker in small cell lung cancer
APMIS
(2013) - et al.
Prognostic significance of urokinase plasminogen activator receptor and its cleaved forms in blood from patients with non-small cell lung cancer
APMIS
(2009) - et al.
Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration
PLoS Med
(2012) - et al.
The cancer degradome: proteases and cancer biology
(2008)
Plasminogen activation and cancer
Thromb Haemost
Prognostic relevance of carbohydrate antigen 19–9 levels in patients with advanced biliary tract cancer
Cancer Epidemiol Biomarkers Prev
Cleaved forms of the urokinase plasminogen activator receptor in plasma have diagnostic potential and predict postoperative survival in patients with ovarian cancer
Clin Cancer Res
Urokinase-catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor
Biochem J
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