Cathepsins B, H and L have been shown to participate in processes of tumor growth, vascularization, invasion and metastasis. Their levels in tumor tissue extracts can provide useful clinical information to predict disease-free and overall survival in breast, lung, colorectal, brain and head and neck cancer patients. Recently we have found that both cysteine cathepsins and their endogenous protein inhibitors stefins and cystatin C can also predict prognosis when measured extracellularly. In melanoma and colorectal cancer patients high serum levels of cathepsins B and H correlated with shorter survival. Similarly, increased extracellular levels of stefins A and B and cystatin C correlated significantly with high risk of adverse outcome in cancer patients. However, the cathepsin B/cystatin C complex was found to be less abundant in sera of patients with malignant tumors than in those with benign diseases or in healthy controls, suggesting an imbalance between the enzyme and its inhibitor in cancer patients.

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Cysteine proteinase cathepsin S (Cat S) is expressed mainly in lymphatic tissues and has been characterised as a key enzyme in major histocompatibility complex class II (MHC-II) mediated antigen presentation. Cat S has been measured in tissue cytosols of lung parenchyma, lung tumours and lymph nodes and in sera of patients with lung tumours and of healthy controls, by specific enzyme-linked immunosorbent assay (ELISA). A difference in Cat S level was found between tumour and adjacent control tissue cytosols of 60 lung cancer patients (median 4.3 vs. 2.8 ng mg−1protein). In lymph nodes obtained from 24 patients of the same group, the level of Cat S was significantly higher than in tumours or lung parenchyma (P< 0.001). Additionally, significantly higher levels were found in non-infiltrated than in infiltrated lymph nodes (median 16.6 vs 7.5 ng mg−1protein). Patients with low levels of Cat S in tumours and lung parenchyma exhibited a significantly higher risk of death than those with high levels of Cat S (P= 0.025 – tumours;P= 0.02 – parenchyma). Immunohistochemical analysis (IHA) of lung parenchyma revealed a staining reaction in alveolar type II cells, macrophages and bronchial epithelial cells. In regional lymph node tissue, strong staining of Cat S was found in lymphocytes and histiocytes. Nevertheless, Cat S was detected also in tumour cells, independently of their origin. Our results provide evidence that Cat S may be involved in malignant progression. Its role, however, differs from that of the related Cats B and L and could be associated with the immune response rather than with remodelling of extracellular matrix. © 2001 Cancer Research Campaign  http://www.bjcancer.com

Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of nonsmall 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, 1.2fold, 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 tumourassociated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low-and high-risk patients with NSCLC.

Summary In order to evaluate the role of cysteine peptidase cathepsin H (Cath H) in human lung cancer its protein levels were determined in 148 pairs of lung tumour tissue and adjacent non-tumourous lung parenchyma using the enzyme-linked immunosorbent assay technique. Additionally, Cath H levels were determined in sera of 171 patients with malignant tumours, 34 patients with benign lung diseases and 47 healthy controls. The median level of Cath H in tumour tissue was 0.64 times that in the corresponding lung parenchyma. Relating tumour levels with histological type we found higher Cath H levels in small-cell and adenocarcinomas and lower levels in squamous cell carcinoma, large-cell carcinoma and secondary tumours. A significant difference in Cath H level between lung tumour tissue and non-tumourous lung parenchyma was associated with the group of cigarette smokers (156 vs 263 ng mg -1 protein, P < 0.001). For this group of patients Cath H tumour levels correlated with the survival rate, while for the entire patient population this was not the case. Smokers with high tumour levels of Cath H experienced poor survival. Cath H was significantly higher in sera of patients with malignant and benign lung diseases than in control sera (P < 0.001). The increase was significant for all histological types, being the highest in small-cell and squamous cell carcinomas. Our study reveals that in lung tumours there is different behaviour of Cath H compared with other cysteine peptidases, e.g. cathepsin B and cathepsin L. Variations between tissue and serum levels of Cath H indicate either reduced expression or enhanced secretion of this enzyme in lung tumours.