Prognostic significance of growth factors and the urokinase-type plasminogen activator system in pancreatic ductal adenocarcinoma.
OBJECTIVE
To determine the diagnostic and prognostic significance of growth factors and the urokinase-type plasminogen activator (uPA) system in pancreatic ductal adenocarcinoma (PDAC) using a multigene assay.


METHODS
Messenger RNA (mRNA) expression of 15 genes from epidermal growth factor receptor, insulin-like growth factor (IGF), and uPA families were measured in 46 PDAC tissue samples using quantitative real-time reverse transcription-polymerase chain reaction. These results were compared with those of the uninvolved adjacent (AP) tissue and benign mucinous cystadenomas (BMC). The mRNA expression was evaluated using logistic regression and receiver operating characteristic area under the curve (ROC AUC) analyses. Their relationship with prognosis was tested by Cox regression multivariate analysis.


RESULTS
All genes were overexpressed in most of the PDAC tissue. When compared with AP tissue, the median expression values for IGF-binding protein 3 (IGFBP-3) and uPA receptor (uPAR) was 9.8- and 9.6-fold, respectively. Expression levels of uPA, uPAR, IGF-I, and IGFBP-3 mRNA were significantly greater in PDAC than in BMC. The IGFBP-3 mRNA expression demonstrated greatest ROC AUC values for PDAC versus AP tissue (ROC AUC, 0.745; 95% confidence interval [CI], 0.65-0.86); whereas ROC AUC values were greatest for uPAR when PDAC was compared with BMC (ROC AUC, 0.846; 95% CI, 0.76-0.94). The combination of uPA, uPAR, and IGF-I significantly improved discriminatory power (ROC AUC, 0.965; 95% CI, 0.93-1.00). The IGFBP-3, uPA, plasminogen activator inhibitor-2, and International Union Against Cancer stage had a significant influence on survival, but the effect of IGFBP-3 was lost after multivariate stepwise analysis.


CONCLUSIONS
These results indicate that there is an influence of IGF system in tumor progression from BMC to PDAC, whereas the uPA/uPAR system has the greater influence on survival in PDAC.
Xue
Aiqun
A
Department of Surgery, The University of Sydney, Sydney, Australia.
Scarlett
Christopher J
CJ
Jackson
Christopher J
CJ
Allen
Barry J
BJ
Smith
Ross C
RC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018291:Cystadenoma, Mucinous / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D012372:ROC Curve; D011956:Receptors, Cell Surface / Q000235:genetics; D017451:Receptors, Somatomedin / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013002:Somatomedins / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; D013002:Somatomedins; D066246:ErbB Receptors; D014568:Urokinase-Type Plasminogen Activator