Urokinase-type plasminogen activator is a marker of aggressive phenotype and an independent prognostic factor in mismatch repair-proficient colorectal cancer

The aim of this study was to determine the prognostic significance of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in colorectal cancer stratified by mismatch repair status and to determine their contribution to the aggressive phenotype predicted by loss of E-cadherin and apoptosis protease activating factor-1 (APAF-1). Immunohistochemistry for uPA and uPAR was performed on a tissue microarray comprising 811 mismatch repair-proficient and 164 mismatch repair-deficient colorectal cancers. Immunoreactivity was scored semiquantitatively and the interobserver agreement between multiple pathologists was determined. Optimal cutoff scores for uPA and uPAR positivity were obtained by receiver operating characteristic curve analysis. Agreement between pathologists was excellent for uPA and uPAR. Cutoff scores of 60% for uPA and 75% for uPAR were validated by resampling of the data. In mismatch repair-proficient colorectal cancer, overexpression of uPA and uPAR was associated with advanced pT stage (P = .009, both), an infiltrating margin (P = .009 and P = .033, respectively), and poor prognosis (P = .002 and P < .001, respectively). uPA, but not uPAR, maintained its significant prognostic effect in multivariable analysis (P = .037). In addition to loss of APAF-1 (P = .002) and E-cadherin (P < .001), uPA independently predicted an infiltrating margin (P = .016). Our findings suggest that uPA, but not uPAR, is an independent prognostic factor and that this negative effect on survival is relevant specifically for mismatch repair-proficient colorectal cancers. Moreover, the combination of uPA with E-cadherin and APAF-1 is linked to an aggressive tumor phenotype and highly predictive of an infiltrating growth pattern.