Top

International Journal of Clinical Oncology

Published in:

01-12-2014 | Original Article

A retrospective study of urokinase-type plasminogen activator receptor (uPAR) as a prognostic factor in cancer of the uterine cervix

Authors: Toru Sasaki, Hirotaka Nishi, Chie Nagata, Takeshi Nagai, Toshitaka Nagao, Fumitoshi Terauchi, Keiichi Isaka

Published in: International Journal of Clinical Oncology | Issue 6/2014

Abstract

Background

Hypoxia occurs during the development of uterine cervical cancer and is considered to correlate with its invasion. Hypoxia promotes both the invasiveness and the metastasis of cancer cells through urokinase-type plasminogen activator receptor (uPAR) expression. The aim of this study was to evaluate the correlation between uPAR mRNA level and clinical prognostic factors of uterine cervical cancer.

Methods

We performed a retrospective review of 59 patients with cervical cancer and 9 subjects with normal cervical tissues. Total RNA was isolated from tissues of the uterine cervix surgically removed from patients. The mRNA of uPAR could be measured by real time PCR (RT-PCR). Histopathological factors such as histopathological type, cervical stromal, parametrial, lymphovascular, and uterine corpus invasions, metastasis to the pelvic lymph nodes, and pTNM stage were confirmed by two pathologists. The examined prognostic factors alongside the histopathological ones were FIGO clinical stage, hemoglobin level, serum level of SCC, and the effect on clinical outcomes. These factors were statistically evaluated by Fisher’s exact test, log-rank test, and ROC analysis. Immunohistochemical staining with anti-uPAR monoclonal antibody was also performed.

Results

In uterine cervical cancer, overexpression of uPAR mRNA was significantly related to shorter disease-free survival (p = 0.0396). However, the other clinical prognostic and histopathological factors were not related to uPAR mRNA expression level. Immunohistochemical staining showed that positive staining for uPAR was histologically localized on the membrane of carcinoma cells. However, the staining was not very intense.

Conclusions

Overexpression of uPAR mRNA may be a prognostic factor in cancer of the uterine cervix.

CANCERMondial, GLOBOCAN 2008. (2013) Section of Cancer Information, International Agency for Research on Cancer. Available at: http://globocan.iarc.fr/

Nordsmark M, Overgaard M, Overgaard J (1996) Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41:31–39PubMedCrossRef

Höckel M, Schlenger K, Aral B et al (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56:4509–4515PubMed

Dass K, Ahmad A, Azmi AS et al (2008) Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 34:122–136PubMedCrossRef

Kwaan HC, McMahon B (2009) The role of plasminogen–plasmin system in cancer. Cancer Treat Res 148:43–66PubMedCrossRef

Büchler P, Reber HA, Tomlinson JS et al (2009) Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer. Neoplasia 11:196–206PubMedCentralPubMed

Kumano M, Miyake H, Muramaki M et al (2009) Expression of urokinase-type plasminogen activator system in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Urol Oncol 27:180–186PubMedCrossRef

Kotzsch M, Bernt K, Friedrich K et al (2010) Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma. Histopathology 57:461–471PubMedCrossRef

Smith R, Xue A, Gill A et al (2007) High expression of plasminogen activator inhibitor-2 (PAI-2) is a predictor of improved survival in patients with pancreatic adenocarcinoma. World J Surg 31:493–502PubMedCrossRef

10.

Zhang L, Zhao ZS, Ru GQ et al (2006) Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer. World J Gastroenterol 12:3970–3976PubMedCentralPubMed

11.

Nishi H, Kuroda M, Isaka K (2013) Estrogen and estrogen receptor induce matrix metalloproteinase-26 expression in endometrial carcinoma cells. Oncol Rep 30:751–756PubMed

12.

Hasegawa E, Ito H, Hasegawa F et al (2012) Expression of leukemia inhibitory factor in the endometrium in abnormal uterine cavities during the implantation window. Fertil Steril 97:953–958PubMedCrossRef

13.

SAS Institute (1985) SAS user’s guide: statistics, Version5. SAS Institute, Cary, pp 529–557

14.

Ying J, Guo L, Qiu T et al (2013) Diagnostic value of a novel fully automated immunochemistry assay for detection of ALK rearrangement in primary lung adenocarcinoma. Ann Oncol 24(10):2589–2593PubMedCrossRef

15.

Foca C, Moses EK, Quinn MA et al (2000) Differential mRNA expression of urokinase-type plasminogen activator, plasminogen activator receptor and plasminogen activator inhibitor type-2 in normal human endometria and endometrial carcinomas. Gynecol Oncol 79:244–250PubMedCrossRef

16.

Halamkova J, Kiss I, Pavlovsky Z et al (2011) Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients. Neoplasma 58:377–385PubMedCrossRef

17.

Cantero D, Friess H, Deflorin J et al (1997) Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 75:388–395PubMedCentralPubMedCrossRef

18.

Almasi CE, Høyer-Hansen G, Christensen IJ et al (2005) Prognostic impact of liberated domain I of the urokinase plasminogen activator receptor in squamous cell lung cancer tissue. Lung Cancer 48:349–355PubMedCrossRef

19.

Friess H, Cantero D, Graber H et al (1997) Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Gastroenterology 113:904–913PubMedCrossRef

20.

Lund IK, Illemann M, Thurison T et al (2011) uPAR as anti-cancer target: evaluation of biomarker potential, histological localization, and antibody-based therapy. Curr Drug Targets 12:1744–1760PubMedCrossRef

21.

Hildenbrand R, Niedergethmann M, Marx A et al (2009) Amplification of the urokinase-type plasminogen activator receptor (uPAR) gene in ductal pancreatic carcinomas identifies a clinically high-risk group. Am J Pathol 174:2246–2253PubMedCentralPubMedCrossRef

22.

Bianchi E, Cohen RL, Thor AT et al (1994) The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res 15:861–866

23.

Pyke C, Kristensen P, Ralfkiaer E et al (1991) Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 138:1059–1067PubMedCentralPubMed

24.

Arvelo F, Cotte C (2009) Hypoxia in cancer malignity. Review. Inv Clin 50:529–546

25.

Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16:5928–5935PubMedCentralPubMedCrossRef

Title: A retrospective study of urokinase-type plasminogen activator receptor (uPAR) as a prognostic factor in cancer of the uterine cervix
Authors: Toru Sasaki
Hirotaka Nishi
Chie Nagata
Takeshi Nagai
Toshitaka Nagao
Fumitoshi Terauchi
Keiichi Isaka
Publication date: 01-12-2014
Publisher: Springer Japan
Published in: International Journal of Clinical Oncology / Issue 6/2014
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-014-0664-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2014

Local control and prognostic significance of transarterial treatment for limited recurrence of ovarian cancer as third-line and beyond therapy

Long-term changes in renal function outcomes following radical cystectomy and urinary diversion

The effects of low- and high-dose-rate brachytherapy on depressive symptoms in prostate cancer patients

Development of an integrated support system for hereditary cancer and its impact on gynecologic services

Diagnostic accuracy of FDG-PET cancer screening in asymptomatic individuals: use of record linkage from the Osaka Cancer Registry

Tamoxifen versus tamoxifen plus doxorubicin and cyclophosphamide as adjuvant therapy for node-positive postmenopausal breast cancer: results of a Japan Clinical Oncology Group Study (JCOG9401)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer