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 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.

Cystatin C – A Fast and Reliable Biomarker for Glomerular Filtration Rate in Head and Neck Cancer Patients

“…Correspondingly, data concerning the role of cystatin C in HNC patients is likewise conflicting. While one report showed increased levels of serum cystatin C in HNC patients when compared to healthy controls [35], suggesting a pathological role of cystatin C in HNC, another investigation demonstrated that high levels of cystatin C in tumor tissue had a protective effect, being associated with prolonged survival [32]. Similar results were published for breast [15,16] and lung cancer [11].…”

Serum cathepsin K and cystatin C concentration in patients with advanced non-small-cell lung cancer during chemotherapy.

“…Moreover, cystatin C is thought to play a role in protein homeostasis in the extracellular compartment, inhibiting inappropriate hydrolytic degradation by proteinases released from dying cells [16]. Cystatin C may also be released from infiltrated inflammatory cells such as macrophages and neutrophils [17]. Higher serum concentrations of Cyst C were also determined in patients with ovarian cancer [18], colorectal cancer and melanoma [19] in comparison with healthy people.…”

“…According to Werle and Kos [14,17] higher total concentrations of Cyst C found in sera of patients with lung, colorectal and melanoma cancer suggested the enhanced secretion of cystatin C from tumor cells, increasing at the same time the intracellular proteolytic potential of cysteine proteases. Moreover, increased levels of cystatin C in tumor tissues have been shown to correlate with favorable prognosis of cancer patients [20][21][22].…”

Identification of a silicatein(-related) protease in the giant spicules of the deep-sea hexactinellidMonorhaphis chuni

“…The 96 amino acid-long deduced protein (termed CYTA_SUBDO) has a size of 10·828·Da and a pI of 6.4. The sponge cystatin shares highest sequence similarity with the human sequences cystatin A and cystatin B, with an 'expect value' (Coligan et al, 2000) of 3e -04 [cystatin B (Joensuu et al, 2007); cystatin A (Werle et al, 2006)]. The sponge cystatin (A) Protein extracts were prepared from the outer lamellar region of the spicules (la; lane a) or from total spicule (to; lane b) and size separated by 10% SDS-PAGE.…”