Differential expression levels of urokinase-type plasminogen activator and cathepsin D in locally advanced laryngeal squamous cell carcinoma: Clinical implications

Abstract

The expression levels and the prognostic impact of urokinase-type plasminogen activator (uPA) and cathepsin D (CD) were evaluated in patients with locally advanced laryngeal squamous cell carcinoma (LSCC). uPA and CD protein levels were determined by immunoluminometric or immunoenzymatic assays in the cytosol of paired sets of tumor tissues and corresponding adjacent normal mucosa (NLM) from 57 patients with stage III/IV LSCC and were correlated with a number of clinicobiological parameters of this tumor including anatomical site, tumor grade, nodal status, clinical stage, DNA ploidy, proliferation rate, and patient outcome. Median uPA levels were significantly higher in LSCC than in NLM (1.8 ng/mg of protein vs 0.3 ng/mg; p<0.001) whereas median CD levels were not significantly increased in tumor tissue compared to NLM (24 pmol/mg vs 19 pmol/mg, p=0.063). No significant correlation was observed between uPA and CD concentrations in tumor tissues (r=-0.1; p=0.4). Furthermore, the distribution analysis of uPA and CD in tumors showed no correlation between expression levels of these proteinases and the parameters mentioned above including patient outcome. However, when data were matched according to each parameter examined it was observed that the differences in uPA content between LSCC and NLM, expressed as uPA tumor/normal tissue ratio (T/M), were more marked in clinically advanced and/or aggressive forms of LSCC (i.e., node positive, stage IV, poorly and moderately differentiated, aneuploid multiclonal, low S-phase, subglottis tumors). These data suggest that in such tumors altered regulation of uPA may occur to a greater extent than in less aggressive and less advanced forms of LSCC. This phenomenon was not observed for CD. However, in tumors with a high proliferation rate, in stage IV tumors as well as in those located in the supraglottis, CD levels were significantly higher than those found in the corresponding NLM (p=0.008, p=0.02 and p=0.03, respectively). In conclusion, uPA is highly expressed in locally advanced LSCC and appears to be implicated in some key events of progression of this tumor such as local invasion and/or nodal involvement, whereas CD does not seem to have a role in promoting these processes. Nevertheless, neither of these proteinases seem to be prognostically useful in patients with stage III/IV tumors.