title: Cystatins in non-small cell lung cancer: tissue levels, localization and relation to prognosis.
abstract: Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of non-small cell lung cancer (NSCLC) the protein level, cysteine protease activity (CPI) and localization of type I (stefins A and B) and type II (C, E/M and F) cystatins were defined in tumours and control lung counterparts from 165 patients. The medians of CPI activity, stefins A and B were significantly greater in tumour than in lung tissue (2.1-fold, 1.7-fold, 1.2-fold, respectively, all p<0.001). The median levels of cystatin C and cystatin E/M were lower in tumour tissue (0.9-fold, p=0.06; 0.6-fold, p<0.01). In all the samples the levels of cystatin F were below the detection limit. Immunohistochemical analysis revealed the presence of all cystatins in tumour cells and infiltrated inflammatory cells such as macrophages and neutrophils. In univariate survival analysis patients with high levels of stefin A, stefin B and CPI activity exhibited a better survival probability (p=0.05, p=0.05, p<0.01, respectively). In contrast, cystatins C and E/M provided no prognostic information. In multivariate analysis the most powerful predictor of survival was the pTNM stage (p<0.0001; RR 3.5), followed by stefin A, stefin B and CPI activity (all p=0.03; RR 1.5). Our results suggest that only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low- and high-risk patients with NSCLC.
authors.affiliation: Abteilung für Klinische Chemie und Bakteriologie, Thoraxklinik Heidelberg gGmbH, D-69117 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Werle
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schanzenbächer
authors.forename: Tamara Turensek
authors.initials: TT
authors.lastname: Lah
authors.forename: Eileen
authors.initials: E
authors.lastname: Ebert
authors.forename: Britta
authors.initials: B
authors.lastname: Jülke
authors.forename: Werner
authors.initials: W
authors.lastname: Ebert
authors.forename: Werner
authors.initials: W
authors.lastname: Fiehn
authors.forename: Klaus
authors.initials: K
authors.lastname: Kayser
authors.forename: Eberhard
authors.initials: E
authors.lastname: Spiess
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrahamson
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality*; D055316:Cystatin C; D055332:Cystatin M; D015891:Cystatins / Q000096:biosynthesis* / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality*; D008875:Middle Aged; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C525030:CST3 protein, human; C525104:CST6 protein, human; C116891:CST7 protein, human; D055316:Cystatin C; D055332:Cystatin M; D015891:Cystatins