Cathepsin B, plasminogenactivator-inhibitor (PAI-1) and plasminogenactivator-receptor (uPAR) are prognostic factors for patients with non-small cell lung cancer

B. Werle, M. Kotzsch, T. T. Lah, J. Kos, D. Gabrijelcic-Geiger, E. Spiess, J. Schirren, Werner Ebert, W. Fiehn, T. Luther, V. Magdolen, M. Schmitt, N. Harbeck

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57 Scopus citations

Abstract

To evaluate the possible role of cysteine proteases and serine proteases, as well as their respective inhibitors and receptors, as new prognostic factors in NSCLC, we examined, for the first time, 10 biological parameters related to three proteolytic systems within a homogeneous collective of 147 cases of NSCLC. Activities (cath BAT, cath BA7.5) and protein levels of cath BC, cath LC, uPA, PAI-1, uPAR [measured by three different assays uPAR (ADI), uPAR (HD13), uPAR (IIIF10)] and TF were measured in homogenates of lung tumour tissue and corresponding non-malignant lung parenchyma. Total cath B activity (cath BAT) and enzymatic activity of the fraction of cath B, which is stable and active at pH 7.5 (cath B A7.5), were determined by a fluorogenic assay using synthetic substrate Z-Arg-Arg-AMC. The concentrations of cath BC, cath L C, uPA, PAI-1, uPAR and TF were determined by ELISAs. uPAR was determined using three different ELISA formats. The median levels of cath B AT (5.1-fold), cath BA7.5 (2.5-fold), cath BC, (8.5-fold), cath LC (6.6-fold), uPA (6.5-fold), PAI-1 (4.2-fold), uPAR (ADI) (2.2-fold), uPAR (HD13) (4.0-fold) and uPAR (IIIF10)(2.6-fold) were higher in tumour tissue compared to the lung parenchyma. Cath BAT, cath BA7.5 and cath BC in primary tumours correlated with lymph node metastases. Regarding histologies, the concentration of PAI-1 seems to be associated with the histological cell types of NSCLC. We found the highest values of PAI-1 in large cell carcinoma > SCC, AC > carcinoid and lowest values in metastases of primary tumours of other organs. Only PAI-1 was significantly increased in poorly-differentiated cells (G3) compared to well- and moderately- differentiated cells (G1/G2). PAI-1 significantly correlated with cath BAT and cath BA7.5 with uPAR (ADI), uPAR (HD13), uPAR (IIIF10) with uPA, and only weakly with TF, but not with cath B C and cath LC. Significant correlations with overall survival in the total population of NSCLC patients were observed in univariate analysis for cath BAT, cath BC, PAI-1, uPAR (ADI), uPAR (HD13), and uPAR (IIIF10). Cath LC was not significantly associated with poor prognosis. Regarding the histological tumour type, only in patients with squamous cell carcinomas did cath BA7.5 and PAI-1 remain significant prognostic factors. In multivariate survival analysis only two proteolytic factors, PAI-1 and uPAR (III10F), stayed significant. In conclusion, among 10 biological parameters evaluated within the same cohort of patients, only PAI-1, uPAR (ADI), uPAR (HD13), uPAR (IIIF10), cath BAT and cath BC are prognostic factors for overall survival of NSCLC patients. Moreover, PAI-1 and uPAR (IIIF10) add independent prognostic information with regard to established clinical and histomorphological factors in NSCLC.

Original languageEnglish
Pages (from-to)4147-4161
Number of pages15
JournalAnticancer Research
Volume24
Issue number6
StatePublished - Nov 2004
Externally publishedYes

Keywords

  • Cathepsin B (cath B)
  • Non-small cell lung cancer (NSCLC)
  • Plasminogenactivator-inhibitor (PAI-1)
  • Plasminogenactivator-receptor (uPAR)
  • Prognosis

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