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Sebzda T, Gnus J, Dziadkowiec B, Latka M, Gburek J. Diagnostic usefulness of selected proteases and acute phase factors in patients with colorectal adenocarcinoma. World J Gastroenterol 2021; 27:6673-6688. [PMID: 34754160 PMCID: PMC8554409 DOI: 10.3748/wjg.v27.i39.6673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/07/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uncontrolled growth and loss of control over basic metabolic functions, leading to invasive proliferation and metastases, are the salient traits of malignant tumors in general and colorectal cancer in particular. Invasion and metastases hinder effective tumor treatment. While surgical techniques and radiotherapy can be used to remove tumor focus, only chemotherapy can eliminate dispersed neoplastic cells. However, the efficacy of the latter method is limited in the advanced stages of the disease. Therefore, recognition of the mechanisms involved in neoplastic cell spreading is indispensable for developing effective therapies.
AIM To use a number of biomarkers involved in cancer progression and identify a panel that could be used for effective early diagnosis.
METHODS We recruited 185 patients with colorectal adenocarcinoma (98 men, 87 women with median age 63). Thirty-five healthy controls were sex and age-matched. Dukes’ staging was as follows: A = 22, B = 52, C = 72, D = 39. We analyzed patients' blood serum before surgery. We determined: (1) Cathepsin B (CB) with Barrett's method (fluorogenic substrate); (2) Leukocytic elastase (LE) in a complex with alpha 1 trypsin inhibitor (AAT) using the immunoenzymatic MERCK test; (3) Total sialic acid (TSA) with the colorimetric periodate-resorcinol method; (4) Lipid-bound sialic acid (LASA) with the colorimetric Taut's method; and (5) The antitrypsin activity (ATA) employing the colorimetric test.
RESULTS In patients, the values of the five biochemical parameters were as follows: CB = 16.1 ± 8.8 mU/L, LE = 875 ± 598 µg/L, TSA = 99 ± 31 mg%, LASA = 0.68 ± 0.33 mg%, and ATA = 3211 ± 1504 U/mL. Except for LASA, they were significantly greater than those of controls: CB = 11.4 ± 6.5 mU/L, LE = 379 ± 187 µg/L, TSA = 71.4 ± 15.1 mg%, LASA = 0.69 ± 0.28 mg%, and ATA = 2016 ± 690 U/mL. For CB and LASA, the differences between the four Dukes’ stages and controls were not statistically significant. The inter-stage differences for CB and LASA were also absent. The receiver operating characteristic (ROC) analysis revealed the potential diagnostic value of CB, TSA, and ATA. The area under ROC, sensitivity, and specificity for these three parameters were: 0.85, 72%, 90%; 0.75, 66%, 77%; and 0.77, 63%, 84%, respectively. The sensitivity and specificity for the three-parameter panel CB-TSA-ATA were equal to 88.2% and 100%, respectively.
CONCLUSION The increased value of CB, TSA, and ATA parameters are associated with tumor biology, invasion, and metastasis of colorectal cancer. The presented evidence suggests the potential value of the CB-TSA-ATA biochemical marker panel in early diagnostics.
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Affiliation(s)
- Tadeusz Sebzda
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw 50-368, Poland
| | - Jan Gnus
- Department of Physiotherapy, Wroclaw Medical University, Wroclaw 50-355, Poland
| | - Barbara Dziadkowiec
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw 50-368, Poland
| | - Miroslaw Latka
- Department of Biomedical Engineering, Wroclaw University of Science and Technology, Wroclaw 50-370, Poland
| | - Jakub Gburek
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Wroclaw 50-556, Poland
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Rudzińska M, Parodi A, Soond SM, Vinarov AZ, Korolev DO, Morozov AO, Daglioglu C, Tutar Y, Zamyatnin AA. The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance. Int J Mol Sci 2019; 20:3602. [PMID: 31340550 PMCID: PMC6678516 DOI: 10.3390/ijms20143602] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 12/21/2022] Open
Abstract
Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.
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Affiliation(s)
- Magdalena Rudzińska
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Alessandro Parodi
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Surinder M Soond
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Andrey Z Vinarov
- Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia
| | - Dmitry O Korolev
- Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia
| | - Andrey O Morozov
- Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia
| | - Cenk Daglioglu
- Izmir Institute of Technology, Faculty of Science, Department of Molecular Biology and Genetics, 35430 Urla/Izmir, Turkey
| | - Yusuf Tutar
- Faculty of Pharmacy, University of Health Sciences, 34668 Istanbul, Turkey
| | - Andrey A Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.
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Yan Y, Zhou K, Wang L, Wang F, Chen X, Fan Q. Clinical significance of serum cathepsin B and cystatin C levels and their ratio in the prognosis of patients with esophageal cancer. Onco Targets Ther 2017; 10:1947-1954. [PMID: 28435284 PMCID: PMC5388217 DOI: 10.2147/ott.s123042] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The main purpose of this study was to analyze the serum cathepsin B (CTSB) and cystatin C (CysC) levels in patients with esophageal carcinoma and their correlation with the clinical indices and prognosis. METHODS The serum levels of CTSB and CysC from 56 patients with esophageal carcinoma and 30 healthy donors were determined preoperatively by using enzyme-linked immunosor-bent assay. The correlation between CTSB and CysC was evaluated by Spearman correlation coefficient test. Kaplan-Meier survival curves were plotted, while the survival rates were compared using the log-rank test. Univariate and multivariate analyses of prognostic factors for survival were performed using the Cox proportional hazard regression model with a 95% confidence interval. RESULTS CTSB (38.35±4.3 ng/mL) and CysC (703.96±23.6 ng/mL) levels were significantly higher in the sera of the patients than in controls. A significant correlation was observed between CTSB and CysC (r=0.754, P<0.001). The levels of CTSB and CysC/CTSB in the patient serum significantly correlated with the T status. CysC/CTSB ratio was also found to be significantly correlated with lymph node metastasis. None of the parameters were observed to be related to CysC, including age, gender, pathologic type, tumor differentiation and tumor invasion depth. Kaplan-Meier analysis showed that patients with higher levels of CysC/CTSB and negative lymph node metastasis experienced significantly longer overall survival time, whereas patients with higher CSTB levels tended to live shorter, although the difference was not statistically significant (P=0.081). CONCLUSION Serum CTSB and CysC levels are of diagnostic significance in esophageal cancer. The ratio of serum CysC/CTSB is prognostic for the survival of esophageal carcinoma patients.
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Affiliation(s)
| | | | | | | | - Xinfeng Chen
- Department of Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
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Hammouda NE, Salah El-Din MA, El-Shishtawy MM, El-Gayar AM. Serum Cystatin C as a Biomarker in Diffuse Large B-Cell Lymphoma. Sci Pharm 2017; 85:9. [PMID: 28282874 PMCID: PMC5388146 DOI: 10.3390/scipharm85010009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 02/28/2017] [Accepted: 02/28/2017] [Indexed: 11/16/2022] Open
Abstract
Elevated serum levels of cystatin C are found to be related to poor outcome and metastatic potential of some malignant disorders. To evaluate the clinical prominence of serum cystatin C in diffuse large B-cell lymphoma (DLBCL), blood samples were obtained from 58 patients at the time of diagnosis and paired blood samples were obtained from 22 patients at the time of remission. Also, serum cystatin C level was measured in matched healthy controls. Serum cystatin C levels were significantly more elevated in DLBCL patients than in controls (p < 0.0001). Furthermore, paired-sample analysis revealed that pretreatment cystatin C levels were reduced significantly in patients who achieved remission after therapy (p = 0.016). High serum cystatin C levels were correlated with age over 60 years (p = 0.049), extra-nodal involvement (p = 0.005) and with high serum lactate dehydrogenase (LDH) (p < 0.013). Elevated serum cystatin C levels were associated with extra-nodal involvement and they were significantly reduced to normal range after the remission. However, Kaplan-Meier curves revealed no survival difference in the pretreatment serum cystatin C levels. Therefore, serum cystatin C may be a novel biomarker that reflects tumor burden in DLBCL but bears no prognostic significance regarding survival.
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Affiliation(s)
- Nada E Hammouda
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Manal A Salah El-Din
- Oncology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
| | - Mamdouh M El-Shishtawy
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Amal M El-Gayar
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
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Zhang X, Hou Y, Niu Z, Li W, Meng X, Zhang N, Yang S. [Clinical significance of detection of cathepsin X and cystatin C in the sera of patients with lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2014; 16:411-6. [PMID: 23945244 PMCID: PMC6000661 DOI: 10.3779/j.issn.1009-3419.2013.08.04] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND AND OBJECTIVE Cathepsin X (Cat X) has been identified as a member of cathepsin family. Studies have shown that Cat X is involved in tumorigenesis and tumor development of various cancers. The aim of this study is to investigate the relationship between the clinicopathological prognosis and the levels of Cat X and cystatin C in the serum of patients with lung cancer. METHODS Blood samples were collected from 84 patients with lung cancer and 36 healthy control subjects. Cat X and cystatin C were determined by quantitative ELISA. RESULTS Cat X and cystatin C levels were significantly higher in the patients with lung cancer than that in the healthy control subjects (P<0.01). Cat X level was correlated with the pathological types of lung cancer (P=0.076). Cystatin C was positively correlated with TNM stage (P=0.01). Furthermore, cystatin C/Cat X was correlated with lymph node metastasis (P=0.058). The patients with high Cat X levels experienced significantly shorter overall survival rates compared with those with low Cat X. Univariate analysis indicated that Cat X and TNM stage were related to overall survival. Multivariate Cox analysis indicated that TNM stage may be used as an independent prognostic variable in patients with lung cancer. CONCLUSIONS Cat X and cystatin C levels were significantly higher in patients with lung cancer. Cat X and cystatin C detection in the sera may contribute to the diagnosis of lung cancer and may be used to evaluate the prognosis of patients with NSCLC.
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Affiliation(s)
- Xuede Zhang
- Department of Respiratory Medicine, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China
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Vižin T, Christensen IJ, Wilhelmsen M, Nielsen HJ, Kos J. Prognostic and predictive value of cathepsin X in serum from colorectal cancer patients. BMC Cancer 2014; 14:259. [PMID: 24725597 PMCID: PMC4021260 DOI: 10.1186/1471-2407-14-259] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 03/31/2014] [Indexed: 12/18/2022] Open
Abstract
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.
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Affiliation(s)
| | | | | | | | - Janko Kos
- Chair of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
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The predictive value of cystatin C in monitoring of B non-hodgkin lymphomas: relation to biochemical and clinical parameters. ISRN ONCOLOGY 2013; 2013:752792. [PMID: 24167744 PMCID: PMC3791566 DOI: 10.1155/2013/752792] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 08/13/2013] [Indexed: 11/17/2022]
Abstract
The predictive value of cystatin C as a marker of course of the disease has been evaluated. Fifty-two pairs of serum samples of patients with B non-Hodgkin lymphoma have been collected at the time of diagnosis and before fourth cycle of chemotherapy. The levels of cystatin C, CRP, β 2M, LDH, and IL-6 in samples have been measured, and clinical parameters of course of the disease (B symptoms, clinical stage, patients' age, and IPI) have been noted. In total patient's group cystatin C levels correlated with β 2M and IPI. In aggressive lymphomas, the inhibitor levels correlated with clinical stage of disease and were significantly higher in patients with elevated LDH activity. In aggressive nodal lymphomas its levels correlated with β 2M, IPI, and clinical stage of disease. The cystatin C level was significantly increased in total group of patients over 60 years old, while in particular types of lymphoma, no statistical significance has been obtained. Our results indicate that cystatin C should be taken into consideration in disease monitoring. However, we expect that the disease-free and overall survival analysis will give the definitive answer about the reliability of cystatin C as an indicator of course of aggressive lymphomas.
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Rokadia HK, Agarwal S. Serum cystatin C and emphysema: results from the National Health and Nutrition Examination Survey (NHANES). Lung 2012; 190:283-90. [PMID: 22286538 DOI: 10.1007/s00408-012-9374-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 01/10/2012] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cystatin C (CysC) is a potent nonorgan-specific cysteine protease inhibitor and may contribute to elastolysis and tissue destruction by a mechanism of protease–antiprotease imbalance. Given the prevalence of CysC in the serum of smokers and its role in tissue destruction, we aimed to evaluate the association between CysC and emphysema. METHODS Pooled cross-sectional data from the National Health and Nutrition Examination Survey 1999–2002 were used. Emphysema and chronic bronchitis were defined by a self-reported history ascertained using standardized questionnaires. Active smokers were defined as self-reported current smokers or measured serum cotinine ≥10 ng/mL. Nonactive smokers with a serum cotinine level >0.05 ng/mL were defined as environmental tobacco smoke (ETS)-exposed. RESULTS The prevalence (95% CI) of emphysema was 1.3% (range = 0.9–1.8%). The mean (SE) CysC level in the emphysema group was significantly higher than in normal controls [1,139 (22) vs. 883 (8) μg/L; p = 0.001]. Upon stratification of the study population by C-reactive protein (CRP) concentrations, we demonstrated a progressive increase in the mean serum CysC level with serially increasing CRP concentrations. Active smokers with emphysema had 115.4 (46.5) μg/L higher mean (SE) CysC levels than the normal controls (p < 0.001). Upon adjusted analysis, we observed that nonactive smokers with significant ETS exposure had 31.2 (15.2) μg/L higher mean (SE) serum CysC levels as compared to ETS unexposed nonactive smokers (p = 0.04). CONCLUSION In a large representative noninstitutionalized US population, we demonstrated an association between emphysema and serum CysC. Active smokers with emphysema had significantly higher CysC levels. These findings suggest that CysC may play a role in the pathogenesis of smoking-related emphysema.
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Affiliation(s)
- Haala K Rokadia
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
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9
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Abstract
Cystatins, the classical inhibitors of C1 cysteine proteinases, have been extensively studied and reviewed in the literature. Over the last 20 years, however, proteins containing cystatin domains but lacking protease inhibitory activities have been identified, and most likely more will be described in the near future. These proteins together with family 1, 2, and 3 cystatins constitute the cystatin superfamily. Mounting evidence points to the new roles that some members of the superfamily have acquired over the course of their evolution. This review is focused on the roles of cystatins in: 1) tumorigenesis, 2) stabilization of matrix metalloproteinases, 3) glomerular filtration rate, 4) immunomodulation, and 5) neurodegenerative diseases. It is the goal of this review to get as many investigators as possible to take a second look at the cystatin superfamily regarding their potential involvement in serious human ailments.
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Affiliation(s)
- Josiah Ochieng
- Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
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10
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Kolwijck E, Massuger LFAG, Thomas CMG, Span PN, Krasovec M, Kos J, Sweep FCGJ. Cathepsins B, L and cystatin C in cyst fluid of ovarian tumors. J Cancer Res Clin Oncol 2009; 136:771-8. [PMID: 19915865 PMCID: PMC2841751 DOI: 10.1007/s00432-009-0716-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2008] [Accepted: 10/19/2009] [Indexed: 01/29/2023]
Abstract
Introduction In cancer, an extracellular and membrane bound localization of cathepsins contribute to the invasion of tumor cells at the basement membrane. Methods This is the first study that explored levels of cathepsins B (CatB), L (CatL) and their inhibitor cystatin C (CysC) in the cystic fluid (CF) of ovarian tumors (n = 110). Results CF contained considerable amounts of CatB, CatL and CysC. Remarkable differences in CatB and CatL and CysC CF levels were found between different histopathological tumor subtypes. Levels of CatB and CysC were significantly higher in CF of malignant serous tumors compared to those found in benign serous tumors (p = 0.010 and p = 0.001 respectively), whereas levels of CatL were significantly higher in CF of malignant mucinous tumors compared to those found in benign mucinous tumors (p = 0.035). CatB and CysC showed a strong correlation in the group of patients with malignant serous tumors (p < 0.001; R = 0.921) suggesting that the increase in CatB might be balanced by a corresponding increase in CysC. Conclusion Further studies are warranted to investigate cathepsins as possible prognostic biomarkers for the aggressiveness of ovarian cancer.
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Affiliation(s)
- Eva Kolwijck
- Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, The Netherlands
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Cysteine cathepsins are not critical for TNF-α-induced cell death in T98G and U937 cells. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2009; 1794:1372-7. [DOI: 10.1016/j.bbapap.2009.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2009] [Revised: 03/24/2009] [Accepted: 04/06/2009] [Indexed: 11/22/2022]
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Abstract
Cathepsins are a class of globular proteases, initially described as intracellular peptide hydrolases, although several cathepsins also have extracellular functions. Cathepsins B, C, F, H, L, K, O, S, V, W, and X are cysteine proteases of the papain family, and represent the largest and best-known class of the cathepsins. Cathepsin G is a serine carboxypeptidases, and cathepsins D and E are aspartic proteases. Cathepsins are synthesized as inactive proenzymes and processed to become mature and active enzymes. Endogenous protein inhibitors, such as cystatins and some serpins, inhibit active enzymes. As primarily lysosomal proteases, cathepsins play important roles in proteolysis during physiological processes, as well as in several diseases. On the basis of their ability to degrade extracellular matrix proteins, cathepsins have been implicated to play a role in invasion and metastasis of colorectal cancer. In the present review, the role of cathepsins in the disease process of colorectal cancers and the correlation of cathepsin expression and activity with clinicopathological features is discussed. Furthermore, we give an overview of the recent developments of cathepsins in animal models and in in vitro experiments of colorectal disease, and provide information on inhibitors of cathepsins as possible therapeutics.
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Keppler D. Towards novel anti-cancer strategies based on cystatin function. Cancer Lett 2006; 235:159-76. [PMID: 15893421 DOI: 10.1016/j.canlet.2005.04.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2005] [Accepted: 04/01/2005] [Indexed: 02/04/2023]
Abstract
Cystatins have recently emerged as important players in a multitude of physiological and patho-physiological settings that range from cell survival and proliferation, to differentiation, cell signaling and immunomodulation. This group of cysteine protease inhibitors forms a large super-family of proteins composed of one, two, three, and, in some species, more than three cystatin domains. Over the last 20 years or so, members of the cystatin super-family have been primarily explored with respect to their capacity to inhibit intracellular cysteine proteases. Yet, this classical mode of action does not fully explain their remarkably diverse biological functions. Due to the space limitations, the author will discuss here the most recent findings that suggest that some of the single-domain, cytoplasmic and cell-secreted cystatins may play important roles in the promotion or suppression of tumor growth, invasion and metastasis. Based on the present understanding of cystatin function, novel avenues for anti-cancer strategies are proposed.
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Affiliation(s)
- Daniel Keppler
- Department of Cellular Biology and Anatomy and Feist-Weiller Cancer Center, School of Medicine, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71130, USA.
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Abstract
Proteases play causal roles in the malignant progression of human tumors. This review centers on the roles in this process of cysteine cathepsins, i.e., peptidases belonging to the papain family (C1) of the CA clan of cysteine proteases. Cysteine cathepsins, most likely along with matrix metalloproteases (MMPs) and serine proteases, degrade the extracellular matrix, thereby facilitating growth and invasion into surrounding tissue and vasculature. Studies on tumor tissues and cell lines have shown changes in expression, activity and distribution of cysteine cathepsins in numerous human cancers. Molecular, immunologic and pharmacological strategies to modulate expression and activity of cysteine cathepsins have provided evidence for a causal role for these enzymes in tumor progression and invasion. Clinically, the levels, activities and localization of cysteine cathepsins and their endogenous inhibitors have been shown to be of diagnostic and prognostic value. Understanding the roles that cysteine proteases play in cancer could lead to the development of more efficacious therapies.
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Strojan P, Svetic B, Smid L, Kos J. Serum cystatin C in patients with head and neck carcinoma. Clin Chim Acta 2005; 344:155-61. [PMID: 15149884 DOI: 10.1016/j.cccn.2004.02.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2003] [Revised: 02/13/2004] [Accepted: 02/13/2004] [Indexed: 10/26/2022]
Abstract
BACKGROUND The balance between proteinases of various classes and their inhibitors was found to be of critical importance for local invasion and metastasizing of tumor cells. The aim of the present study was to determine the changes in the serum cystatin C concentration in patients with squamous cell carcinoma of the head and neck. METHODS In the sera of 34 patients with squamous cell carcinoma of the head and neck, the concentration of cysteine proteinase inhibitor cystatin C was determined using ELISA. The serum samples were collected at diagnosis (group A) and 7 to 407 days (median, 59 days) after the therapy (group B). The sera of 30 healthy blood donors served as controls (group C). RESULTS A significant increase in the median concentration of cystatin C was found in the patients' sera (group A: 573 ng/ml, P<0.0001; group B: 551 ng/ml, P<0.0001) compared to control group C (320 ng/ml), whereas no difference was observed between groups A and B (P>0.05). Cystatin C concentrations in the sera of group A correlated with the site of primary tumor (P=0.035), being higher in the patients with non-laryngeal tumors (658 ng/ml) than in those with larynx primaries (529 ng/ml). There was a significant trend (RS=-0.535, P=0.049) towards lower cystatin C concentrations with an increasing time delay in post-treatment serum sampling (group B), which was observed in the patients with no relapse of the disease and a sampling later than 45 days after the completion of therapy. CONCLUSIONS These results add to the knowledge of the role of cystatin C in invasive behavior of squamous cell carcinoma of the head and neck, and suggest its potential role as a tumor marker in this particular type of cancer.
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Affiliation(s)
- Primoz Strojan
- Department of Radiation Oncology, Institute of Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia
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Troy AM, Sheahan K, Mulcahy HE, Duffy MJ, Hyland JMP, O'Donoghue DP. Expression of Cathepsin B and L antigen and activity is associated with early colorectal cancer progression. Eur J Cancer 2004; 40:1610-6. [PMID: 15196548 DOI: 10.1016/j.ejca.2004.03.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2003] [Revised: 03/04/2004] [Accepted: 03/05/2004] [Indexed: 12/19/2022]
Abstract
Cathepsin B and Cathepsin L are cysteine proteases important in the process of invasion and metastasis. The aim of our study was to assay antigen and activity levels of these enzymes and to correlate these with established clinical and pathological prognostic parameters including patient survival. 99 patients undergoing operations for colorectal cancer were included in this study. We quantitated cathepsin B and L levels in matched normal mucosa and cancer samples using an enzyme-linked immunosorbent assay (ELISA) and specific activity assays and expressed the results as tumour/normal ratios. Significant correlations were found between tumour/normal cathepsin B and L antigen and activity ratios. Cathepsin B and L tumour/normal activity ratios were greater than 1 in early stage disease and there were gradual reductions in cathepsin B (P = 0.02) and L (P = 0.03) activity ratios with advancing tumour stage. Survival of patients with potentially curative disease was inversely related to both cathepsin B (P = 0.007) and L (P = 0.001) activity ratio, in addition to cathepsin L antigen ratio (P = 0.008). Our findings suggest that cysteine proteases play an important role in colorectal cancer progression.
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Affiliation(s)
- A M Troy
- Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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Strojan P, Oblak I, Svetic B, Smid L, Kos J. Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis. Br J Cancer 2004; 90:1961-8. [PMID: 15138478 PMCID: PMC2409457 DOI: 10.1038/sj.bjc.6601830] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
To determine the role of the cysteine proteinase inhibitor cystatin C in the invasive behavior of squamous cell carcinoma of the head and neck (SCCHN), Cystatin C protein level was measured in 82 pairs of primary tumour tissue and adjacent noncancerous mucosa, using the enzyme-linked immunosorbent assay. The median level of cystatin C in tumour tissue was 1.18 times lower than that in corresponding mucosa (P=0.031). In normal mucosa samples, the cystatin C level was influenced by the site of sampling: it was lower in nonlaryngeal tissue samples (oral cavity, oro- or hypopharynx) than in laryngeal samples (P=0.004). The tumour cystatin C level correlated inversely with pN-stage (P=0.047), whereas a trend of lower cystatin C levels was observed in the group with extranodal tumour extension compared to those with no extranodal spread (P=0.069). In univariate analysis, the patients with low tumour cystatin C levels exhibited poor disease-free survival (DFS, P=0.013) and disease-specific survival (DSS, P=0.013). In multivariate analysis, the most powerful predictor of survival was pN-stage (DFS: P=0.040, HR 2.78; DSS: P=0.011, HR 4.36,), followed by the cystatin C level (DFS: P=0.043, HR 0.22; DSS: P=0.067, HR 0.25). When comparing the prognostic strength of cystatin C to that of stefin A, another cysteine proteinase inhibitor, which emerged as the most significant prognosticator for survival in our previous study analysing the same cohort of patients, stefin A proved to be significantly more reliable predictor for both DFS and DSS than cystatin C. Our results indicate that cystatin C is implicated in the invasive behavior of SCCHN, and that there are variations in regulation of proteolytic pathways under nonmalignant conditions, inherent to individual subsites inside the upper aerodigestive tract. The correlation between high cystatin C levels and improved survival concurs with the concept of the protective role of high levels of cysteine proteinase inhibitors in tissue homogenates that has been previously suggested by the survival results in breast and lung carcinoma as well as SCCHN.
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Affiliation(s)
- P Strojan
- Department of Radiotherapy, Institute of Oncology, SI-1000 Ljubljana, Slovenia.
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Berdowska I. Cysteine proteases as disease markers. Clin Chim Acta 2004; 342:41-69. [PMID: 15026265 DOI: 10.1016/j.cccn.2003.12.016] [Citation(s) in RCA: 143] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2003] [Revised: 12/17/2003] [Accepted: 12/17/2003] [Indexed: 01/19/2023]
Abstract
This review comprises issues concerning cysteine cathepsins (CCs): human peptidases belonging to papain family (C1) of clan CA of cysteine proteases: cathepsins B, L, H, S, K, F, V, X, W, O and C. The involvement of these enzymes in physiological and pathological processes is described, especially with respect to their application as diagnostic and prognostic markers. They participate in precursor protein activation (including proenzymes and prohormones), MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction and apoptosis. Cysteine cathepsins upregulation has been demonstrated in many human tumors, including breast, lung, brain, gastrointestinal, head and neck cancer, and melanoma. Besides cancer diseases, they have been implied to participate in inflammatory diseases, such as inflammatory myopathies, rheumatoid arthritis, and periodontitis. Also, certain hereditary disorders are connected with mutations in CCs genes, what is observed in pycnodysostosis resulted from catK gene mutation and Papillon-Lefevre and Haim-Munk syndrome caused by catC gene defect. The potential application of cysteine cathepsins in diagnosis and/or prognosis is discussed in cancer diseases (breast, lung, head and neck, ovarian, gastrointestinal cancers, melanoma), as well as other disorders (periodontitis, rheumatoid arthritis, osteoarthritis).
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Affiliation(s)
- Izabela Berdowska
- Department of Medical Biochemistry, Wroclaw Medical University, 10 Chalubinskiego, 50-368 Wroclaw, Poland.
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Abstract
Using more reliable and sophisticated protein biochemical techniques, it is possible to perform large scale, partly high-throughput characterization of the human proteome. Two-dimensional electrophoresis (2-DE) and mass spectrometry largely contribute to the identification of proteins and peptides. 2-DE has been used to study differential expression of peptides and proteins in various disease entities, searching for new diagnostic and therapeutic targets. However, 2-DE usually requires large amounts of starting material, is time-consuming, and reveals only a fraction of the proteins present in a given sample. More recently, the ProteinChip technology coupled with bioinformatics has gained considerable attention. This technique uses surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI TOF/MS) to screen any protein source for putative disease biomarkers in a spectrum from 2 to 20 kDa. Between 15,500 (low resolution SELDI TOF) and > 400,000 peptides and proteins (high-resolution SELDI-TOF) can be resolved from a small sample volume (microl-range). Several studies have provided evidence that ProteinChip technology is capable of detecting early stage cancer by its unique cancer-specific proteomic finger prints, with sensitivities and specificities reaching far beyond well established serum-based tumor markers. In this review, we summarize the recent developments of proteomics in research and pathology, and critically discuss putative limitations and future applications of disease-specific biomarkers. Special emphasis is put on the former Human Protein Index project.
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Affiliation(s)
- Christoph Röcken
- Department of Pathology, Otto-von-Guericke-University, Leipziger Strasse 44, D-39120 Magdeburg, Germany.
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Jenko S, Dolenc I, Guncar G, Dobersek A, Podobnik M, Turk D. Crystal structure of Stefin A in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo- and exopeptidases. J Mol Biol 2003; 326:875-85. [PMID: 12581647 DOI: 10.1016/s0022-2836(02)01432-8] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Binding of cystatin-type inhibitors to papain-like exopeptidases cannot be explained by the stefin B-papain complex. The crystal structure of human stefin A bound to an aminopeptidase, porcine cathepsin H, has been determined in monoclinic and orthorhombic crystal forms at 2.8A and 2.4A resolutions, respectively. The asymmetric unit of each form contains four complexes. The structures are similar to the stefin B-papain complex, but with a few distinct differences. On binding, the N-terminal residues of stefin A adopt the form of a hook, which pushes away cathepsin H mini-chain residues and distorts the structure of the short four residue insertion (Lys155A-Asp155D) unique to cathepsin H. Comparison with the structure of isolated cathepsin H shows that the rims of the cathepsin H structure are slightly displaced (up to 1A) from their position in the free enzyme. Furthermore, comparison with the stefin B-papain complex showed that molecules of stefin A bind about 0.8A deeper into the active site cleft of cathepsin H than stefin B into papain. The approach of stefin A to cathepsin H induces structural changes along the interaction surface of both molecules, whereas no such changes were observed in the stefin B-papain complex. Carboxymethylation of papain seems to have prevented the formation of the genuine binding geometry between a papain-like enzyme and a cystatin-type inhibitor as we observe it in the structure presented here.
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Affiliation(s)
- Sasa Jenko
- Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Jamova 39, SI-1111 Ljubljana, Slovenia
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Turk V, Turk B, Guncar G, Turk D, Kos J. Lysosomal cathepsins: structure, role in antigen processing and presentation, and cancer. ADVANCES IN ENZYME REGULATION 2002; 42:285-303. [PMID: 12123721 DOI: 10.1016/s0065-2571(01)00034-6] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Vito Turk
- Department of Biochemistry and Molecular Biology, J. Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
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Cimerman N, Mesko Brguljan P, Krasovec M, Suskovic S, Kos J. Serum concentration and circadian profiles of cathepsins B, H and L, and their inhibitors, stefins A and B, in asthma. Clin Chim Acta 2001; 310:113-22. [PMID: 11498076 DOI: 10.1016/s0009-8981(01)00530-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
BACKGROUND In order to determine the effect of asthma on serum concentrations of cathepsins B, H and L, and stefins A and B, the circadian and concentration profiles were followed in steroid-independent and steroid-dependent asthmatics before and after 1-week treatment with methylprednisolone and cyclosporin A. METHODS Serum samples were taken at 4-h intervals throughout a 24-h period. Cathepsin and stefin concentrations were assayed using specific ELISAs. Data were analysed by one-way ANOVA and least squares fit of 24-h cosine. RESULTS Temporal analysis of these proteins revealed little or no significant changes with time over a 24-h period. In comparison to normal sera, cathepsin H concentrations were elevated in all asthmatic patients, concentrations of both stefins were decreased in steroid-independent asthmatics, and stefin A concentrations were increased in steroid-dependent asthmatics before therapy. The effect of methylprednisolone treatment was demonstrated on decreased cathepsin B and increased cathepsin L concentrations in post-therapy serum samples. On the other hand, cyclosporin A treatment led to increased concentrations of cathepsins H and L. However, concentrations of stefins A and B were unaffected. CONCLUSIONS This study associated alterations in balance of serum cysteine proteinases and their inhibitors in asthmatic patients, which has raised the possibility of their involvement in asthma pathogenesis. Validated rhythms of cathepsins and stefins in asthmatic sera exhibited temporal differences, which are too small to influence the time of sampling for their quantitative measurement over the course of a day.
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Affiliation(s)
- N Cimerman
- Department of Biochemical Research and Drug Design, Research and Development Division, KRKA, d.d., Cesta na Brdo 49, 1000 Ljubljana, Slovenia.
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