Assessment of the Roles of Cathepsins B, H and L in the Progression of Colorectal Cancer (original) (raw)
Related papers
Cancer Letters, 1995
Cathepsins, which are secreted by tumour and/or stromal cells, are thought to be involved in the degradative processes of tumour invasion and metastasis. The purpose of our study was to compare the cytosolic content of cathepsin B, L, and D in a series of matched malignant and adjacent normal colorectal tissues. Further we attempted to correlate these different proteinase values to classical clinico-pathological prognostic variables. Cathepsin B, L, and D activities were higher in tumour tissues than in normal mucosa (P c lOd, P c 0.004, P < 0.004, respectively) with median tumour/normal ratios of 7.9, 5.9, and 1.4, respectively. We found no difference in cathepsin B, L, and D activities either as a function of gender (except for cathepsin B values), age at time of surgery, tumour site, tumour differentiation, tumour stage (TNM or Astler-Coller staging system) or whether or not we found a mutinous component. Based on our data, cathepsin B seems to be the most discriminant parameter of the three proteinases that we studied, suggesting that cathepsin B expression may be of critical value in the progression of colorectal cancers,
Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas
British journal of cancer, 2000
Our analyses of cathepsin H activity levels and protein forms in human colorectal cancers compared to matched control mucosa support the concept that altered proteinase expression patterns may reflect both cancer stage and site. Cathepsin H-specific activity was significantly increased in colorectal cancers compared to control mucosa (P = 0.003; n = 77). Highest specific activities and cancer/normal ratios (C/N) for activity were measured in Dukes' B and C stage carcinomas, cancers involved in local spread and invasion to lymph nodes. In contrast, cathepsin B and L activities analysed in the same paired extracts had been shown to be most frequently elevated in earlier stage carcinomas (Dukes' A and B), confirming that cathepsin H demonstrates a distinct pattern of expression during colorectal cancer progression. Although cathepsin H activities were most commonly elevated in Dukes' C cancers at all colon sites, both specific activity and C/N ratios were significantly high...
Cathepsin X in serum from patients with colorectal cancer: relation to prognosis
Radiology and Oncology, 2012
Background. Up-regulation of lysosomal cysteine protease cathepsin X (Cat X) is associated with disorders of the immune system and neurodegenerative diseases, while its role in the development and progression of cancer is less understood. Enhanced secretion of pro-Cat X was observed in malignant processes, and therefore, the level of total serum Cat X rather than the active enzyme may better reflect the tumour status. Patients and methods. Seventy-seven patients with colorectal cancer (CRC) were included in a retrospective study. Blood samples were collected prior to therapy. Using ELISA, the values of total Cat X were measured in serum. Groups of healthy persons (n=77), patients with adenomas (n=77) and patients with non-neoplastic findings (n=77) were included. Results. Significant differences between the group of colorectal patients and the groups of healthy persons, adenoma patients and patients with non-malignant findings could not be shown (p=0.89). Within the group of CRC, higher levels of total Cat X significantly correlated to shorter overall survival (HR=2.08, 95% CI:1.07-4.05, p=0.028). Conclusions. Total serum Cat X could be a useful prognostic indicator for determining survival of patients with CRC. Increased serum levels of total Cat X may reflect more aggressive tumour cell phenotypes and suggest the involvement of Cat X in processes involved in later stages of tumour progression.
Cancer Epidemiology Biomarkers & Prevention, 2010
Background and Aims-Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B activatable imaging agents demonstrate high enzyme activity within intestinal tumors. Methods-We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer-specific and overall mortality according to tumoral expression of cathepsin B. Results-Among 558 participants, 457 (82%) had tumors that expressed cathepsin B (CTSBpositive) and 101 (18%) had tumors that did not express cathepsin B (CTSB-negative). Cathepsin B expression was not associated with disease stage (P=0.19). After a median follow-up of 11.6 years,
Cysteine protease activities and tumor development in human colorectal carcinoma
Cancer research, 1989
Many studies of malignant cells or tissues in culture have implicated cysteine proteases in the progression of malignancy. We have extended these observations by measuring quantitative and qualitative changes in the expression of cathepsin B-like and L-like cysteine proteases during the growth and development of human colorectal carcinomas. Data derived from matched pairs of normal colorectal mucosa and carcinoma tissue from 27 patients demonstrated that both cathepsin B-like and cathepsin L-like specific activities were significantly elevated (P less than 0.005) in the carcinoma tissue, while levels of endogenous cysteine protease inhibitor remained constant. Correlation of cathepsin enzyme activities with different stages of colorectal cancer demonstrated significantly higher cysteine protease activities in individuals with Dukes' A tumors (tumors confined to the bowel wall) than in patients with more advanced tumors (Dukes' B, C, or D tumors) (P less than 0.01-0.05). The ...
International Journal of Cancer, 2009
Previous in vitro studies have identified a nuclear isoform of Cathepsin L. The aim of this study was to examine if nuclear Cathepsin L exists in vivo and examine its association with clinical, pathological and patient outcome data. Cellular localization (nuclear and cytoplasmic) and expression levels v of Cathespin L in 186 colorectal cancer cases using immunohistochemistry. The molecular weight and activity of nuclear and cytoplasmic Cathepsin L in vivo and in vitro were assessed by Western blotting and ELISA, respectively. Epithelial nuclear staining percentage (p 5 0.04) and intensity (p 5 0.006) increased with advancing tumor stage, whereas stromal cytoplasmic staining decreased (p 5 0.02). Using multivariate statistical analysis, survival was inversely associated with staining intensity in the epithelial cytoplasm (p 5 0.01) and stromal nuclei (p 5 0.007). In different colorectal cell lines and in vivo tumors, pro-and active Cathepsin L isoforms were present in both the cytoplasm and nuclear samples, with pro-Cathepsin L at 50 kDa and active Cathepsin L at 25 kDa. Purified nuclear and cytoplasmic fractions from cell lines and tumors showed active Cathepsin L activity. The identification of nuclear Cathepsin L may play an important prognostic role in colorectal disease progression and patient outcome. Moreover, these findings suggest that altering active nuclear Cathepsin L may significantly influence disease progression. ' 2009 UICC Key words: colorectal cancer; cathepsin L; disease progression; survival Colorectal cancer is one of the most common cancers in the Western World. Tumor invasion and metastasis are major causes of treatment failure 1 and this multi-step process involves penetration of host extracellular matrix (ECM) by cancer cells, which invade the host stroma and enter the circulation. The outcome of metastasis is dependent on the interaction between the intrinsic properties of the tumor cells and various host factors, and this balance may vary from patient to patient. 2,3 The ability of tumor cells to invade tissues and metastasize is thought to involve an increased expression and activity of proteases including cathepsins. 4,5 Tumor spread is also correlated with increased levels of these activated enzymes. The cysteine protease, Cathepsin L, is thought to participate in tumor cell invasion, although its exact role remains unknown. 7 The Cathepsin L gene is activated by a variety of growth factors and oncogenes. 8 It is initially synthesized as a 334-amino acid precursor containing a 17-amino acid N-terminal signal peptide followed by a 96-amino acid propeptide. 9-11 Pro-Cathepsin L is an inactive precursor and is processed to a single chain form of mature Cathepsin L, which can be further cleaved to the two-chain forms, linked to a light-chain by disulfide bonds. 12,13 Pro-and active forms of Cathepsin L differ in size depending on the species, tissue and cell line investigated. Colorectal cancers have been profiled based on the levels of different cysteine proteases including Cathepsin L. 14 Using an enzyme-linked immunosorbent assay (ELISA) and specific activity assays, we have previously shown that Cathespin L activity and antigen levels are significantly higher in early versus late stage CRC and that high levels correlate with adverse long-term outcome. 15 However, little is known about Cathepsin L expression and activity in different cellular compartments and about levels of Cathepsin L in different cell types within colorectal cancer tumors. This study investigated the cellular localization (nuclear and cytoplasmic) of Cathepsin L in different stages of colorectal cancer, and correlated results with clinical, pathological and patient follow-up data.
Prognostic and predictive value of cathepsin X in serum from colorectal cancer patients
BMC Cancer, 2014
Background: Cathepsin X is a cysteine protease involved in mechanisms of malignant progression. It is secreted from tumour cells as a proenzyme and may serve to predict the disease status and risk of death for cancer patients. In a previous, pilot, study on 77 colorectal patients we demonstrated the correlation of higher serum levels with shorter overall survival. Methods: 264 patients with colorectal cancer were included in a prospectively accrued multi-centre observational cohort study with the aim of testing novel biomarkers. Blood samples were collected before preoperative large bowel endoscopy and total cathepsin X was measured in sera by ELISA. As a control group we selected at random 77 subjects who had no findings at endoscopy and reported no co-morbidity. Results: The mean level of cathepsin X in cancer patients did not differ from the control levels (23.4 ng/ml ± 6.4 SD vs. 18.8 ng/ml ± 11.4 SD, p > 0.05) and there was no association with age, gender, disease stage, tumour location or CEA. In univariate analysis no association between cathepsin X levels and overall survival was demonstrated for the entire set of patients, however, cathepsin X was associated with survival in a group of patients with local resectable disease (stages I-III) (HR = 1.69, 95% CI: 1.03-2.75, p = 0.03). For this group, multivariate Cox regression analysis showed an association (HR = 3.13, 95% CI: 1.37-7.18, p = 0.003) between high cathepsin X levels and shorter overall survival for patients who did not receive chemotherapy, whereas, for patients who received chemotherapy, there was no association between cathepsin X and survival (HR = 0.51, 95% CI: 0.20-1.33, p = 0.88). Conclusions: Association of cathepsin X levels with overall survival was not confirmed for an entire set of 264 colorectal patients, but for patients in stages I-III with local resectable disease. The significant association of cathepsin X with survival in a group of patients who received no chemotherapy and the absence of this association in the group who received chemotherapy, suggest the possible predictive value for response to chemotherapy. The results have to be confirmed in a further prospective study.
Pharmaceuticals
In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.
Cathepsin B/Cystatin C Complex Levels in Sera from Patients with Lung and Colorectal Cancer
bchm, 2001
A sandwich-type ELISA has been developed for quantification of the complex between the cysteine proteinase cathepsin Β (CB) and its reversible tight-binding inhibitor cystatin C (CC) in normal and pathological sera. The assay is based on a combination of catching Ab (3E1), raised against CB, and a horseradish peroxidase-labelled detection Ab (1A2), raised against CC. Only the CB/CC complex is able to evoke a signal in this assay. The detection limit of the assay was 15.5 ΠΜ and the working range between 31.3-200 nM. The within and between-run coefficients of variance (CV) varied from 4.7% to 9.4% and 11% to 12.8%, respectively, demonstrating satisfactory reproducibility of the method. The concentration of the CB/CC complex was determined in sera from 90 healthy controls, 32 patients with non-cancerous lung diseases, 148 patients with lung and 32 patients with colorectal cancer. The CB/CC complex was significantly less abundant in sera of patients bearing malignant lung tumours than in those with non-cancerous lung diseases or healthy controls (p<0.001). In colorectal cancer sera its level was significantly lower in advanced stages C and D than in early Dukes' stages A and Β (p=0.02). Our results show that the increased levels of CB in malignant sera are not impaired effectively by CC and support the hypothesis of hindered inhibitory capability during cancer progression.