Cathepsin S in tumours, regional lymph nodes and sera of patients with lung cancer: relation to prognosis (original) (raw)

2001, British Journal of Cancer

Cathepsins have been shown to participate in dissolution and remodelling of connective tissue and basement membranes in the processes of tumour growth, invasion and metastasis (Sloane et al, 1994; Kos and Lah, 1998). Increased levels of Cats B and L in tumours and some extracellular fluids are associated with shorter disease-free and overall survival periods and may serve as prognostic factors for cancer patients (Kos and Lah, 1998). The role of another cysteine proteinase, Cat S in tumour progression is less understood. In contrast to Cats B and L, which are active at acidic pH, Cat S retains most of its enzymatic activity at pH 7.0-7.5. Another distinct feature is the substantial elastolytic activity it exhibits at neutral pH (Chapman et al, 1997). Cat S exhibits restricted tissue expression and is present in higher amounts in lymph nodes (Turenšek et al, 1975), spleen and antigen-presenting cells (APCs), including macrophages, dendritic cells and B lymphocytes (Shi et al, 1994; Morton et al, 1995). Its expression was found to be induced by cytokines, such as interferon γ and interleukin 1β (Chapman et al, 1997). Cat S activity appears to be essential in the MHC class II antigen presentation pathway. It specifically degrades the invariant chain (Ii), a MHC class II chaperone, prior to its removal from the MHC class II peptide-binding cleft. This facilitates the loading of antigenic peptides to MHC class II αβ-dimers and subsequent transportation of the complex to the cell surface to initiate MHC class II restricted CD4 + T-cell recognition (Chapman et al, 1997; Pierre and Mellman, 1998). Besides participation in the immune response some other specific functions, associated with high elastolytic activity of Cat S have been proposed. For example, Cat S has been suggested to promote motility of the cilia of conducting airway cells in the lung (Chapman et al, 1997). Additionally, it was found to participate in vascular matrix remodelling and in the formation of the atherosclerotic intima (Sukhova et al, 1998). In rat, Cat S is expressed in thyroid tissue, where a role in processing thyroglobulin and release of thyroid hormone has been proposed (Petancheska and Devi, 1992). Increased expression of Cat S has also been associated with the pathogenesis of Alzheimer disease (Lemere et al, 1995). The aim of the present study was to evaluate the role this enzyme might have in the progression of lung cancer. For this purpose a quantitative method for measuring the level of Cat S in tissue extracts and sera of lung cancer patients was developed and the levels have been tested for their relationship to clinical features, considering especially the correlation with the survival rate for cancer patients. Additionally, the cell types, expressing Cat S in tumours, lung parenchyma and lymph nodes, have been evaluated by IHA. MATERIALS, METHODS AND PATIENTS Antigen, antibodies Human pro-Cat S was produced in E. coli using an inducible T7based expression system (Kopitar et al, 1996