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Giri A, Hong IS, Kwon TK, Kang JS, Jeong JH, Kweon S, Yook S. Exploring therapeutic and diagnostic potential of cysteine cathepsin as targets for cancer therapy with nanomedicine. Int J Biol Macromol 2025; 315:144324. [PMID: 40398760 DOI: 10.1016/j.ijbiomac.2025.144324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 05/05/2025] [Accepted: 05/15/2025] [Indexed: 05/23/2025]
Abstract
Cysteine cathepsins have been discovered to be substantially expressed in multiple types of cancer. They play a key role in the progression and growth of these cancers, rendering them appealing targets for nanoscale delivery and noninvasive diagnostic imaging. This review explores cathepsins from the papain-like enzyme family (C1) within the cysteine peptidase clan (CA), emphasizing the role of cathepsin-responsive nanoparticles in tumor growth. Furthermore, it also explores how nanotechnology can harness cathepsin activity to enable targeted drug delivery, improve tumor imaging, and reduce systemic toxicity. By examining the molecular mechanisms governing cathepsin function and evaluating different nanocarrier systems, this work aims to enhance our understanding of targeted cancer treatment. Despite significant advances, challenges remain in translating these nanomedicine platforms into clinical use, including improving delivery efficiency, biocompatibility, long-term safety, and addressing issues such as interspecies protease variability and scalable nanomanufacturing. Future advancement, integrating advanced biomaterials, patient-derived organoid models, bispecific immune-protease targeting, CRISPR-based cathepsin editing, and artificial intelligence-driven pharmacokinetic modeling and analysis will be critical to fully realizing the clinical potential of cathepsin targeted nanomedicines. These innovations hold promises for advancing precision oncology by overcoming current limitations and improving patient outcomes.
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Affiliation(s)
- Anil Giri
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - In-Sun Hong
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea
| | - Taeg Kyu Kwon
- Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea; Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, 42601, Republic of Korea
| | - Jong-Sun Kang
- Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea
| | - Seho Kweon
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
| | - Simmyung Yook
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
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Buijs SM, Jongbloed EM, van Bergen LEM, Ramakers CRB, Koolen SLW, Mathijssen RHJ, Betjes MGH, Jager A. Pseudo acute kidney injury in patients receiving CDK4/6 inhibitors. Br J Cancer 2025; 132:525-532. [PMID: 39930149 PMCID: PMC11920040 DOI: 10.1038/s41416-025-02951-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/12/2024] [Accepted: 01/30/2025] [Indexed: 03/20/2025] Open
Abstract
INTRODUCTION CDK4/6 inhibitors (CDK4/6i) improve progression-free survival in patients with advanced oestrogen-receptor-positive breast cancer. However, all CDK4/6i may increase creatinine levels, which can indicate kidney injury. In vitro research has shown that CDK4/6i can also inhibit tubular secretion of creatinine, thereby causing the phenomenon 'pseudo-acute kidney injury (pseudo-AKI)'. The incidence of pseudo-AKI is, however, unknown. We aimed to determine this incidence by assessing cystatin C, a protein filtered in the glomerulus without being subject to tubular secretion, in patients with creatinine increase during CDK4/6i treatment. METHODS In this retrospective single-centre cohort study patients with breast cancer who received CDK4/6 inhibitors between January 1st 2017 and December 29th 2023 were screened for the incidence of creatinine increases suggesting potential kidney injury in the first six months of treatment. A significant creatinine increase was defined as 1) a creatinine plasma level of >90 µmol/L in women or >115 µmol/L in men and >10% increase from baseline creatinine plasma level or 2) a creatinine plasma level >1.5 times baseline creatinine or 3) an increase in creatinine plasma level from baseline with >26 µmol/L. Pseudo-AKI was diagnosed if the estimated glomerular filtration rate (eGFR) using cystatin C at the moment of creatinine increase was 1) equal or higher than eGFR using creatinine at baseline and/or 2) at least 25% higher than eGFR using creatinine at the moment of creatinine increase. The primary endpoint was the percentage of patients with pseudo-AKI analysed by means of the binomial probability test. RESULTS Of the 234 patients treated with a CDK4/6i, 41 (17.5%) had creatinine levels indicating an AKI. From 22 of these 41 patients, cystatin C could be determined in retrospectively available serum. Pseudo-AKI was found in 16 out of 22 patients (73%, 95% CI 50-89%). In 5 out of 41 patients (12%) the CDK4/6i dose was unjustly adjusted or the drug was stopped due to creatinine increase. CONCLUSION Pseudo-AKI has a high incidence in patients treated with CDK4/6i. Determining an eGFR based on the cystatin C value should therefore be considered as the first step when creatinine increases during CDK4/6i treatment.
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Affiliation(s)
- Sanne M Buijs
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
| | - Elisabeth M Jongbloed
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Lotte E M van Bergen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Christian R B Ramakers
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Stijn L W Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
- Department of Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Michiel G H Betjes
- Department of Nephrology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Agnes Jager
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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Qu Y, Yao Z, Xu N, Shi G, Su J, Ye S, Chang K, Li K, Wang Y, Tan S, Pei X, Chen Y, Qin Z, Feng J, Lv J, Zhu J, Ma F, Tang S, Xu W, Tian X, Anwaier A, Tian S, Xu W, Wu X, Zhu S, Zhu Y, Cao D, Sun M, Gan H, Zhao J, Zhang H, Ye D, Ding C. Plasma proteomic profiling discovers molecular features associated with upper tract urothelial carcinoma. Cell Rep Med 2023; 4:101166. [PMID: 37633276 PMCID: PMC10518597 DOI: 10.1016/j.xcrm.2023.101166] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 05/16/2023] [Accepted: 08/01/2023] [Indexed: 08/28/2023]
Abstract
Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease monitoring. Here, we investigate the proteomic profile of plasma in 362 UTUC patients and 239 healthy controls. We present an integrated tissue-plasma proteomic approach to infer the signature proteins for identifying patients with muscle-invasive UTUC. We discover a protein panel that reflects lymph node metastasis, which is of interest in identifying UTUC patients with high risk and poor prognosis. We also identify a ten-protein classifier and establish a progression clock predicting progression-free survival of UTUC patients. Finally, we further validate the signature proteins by parallel reaction monitoring assay in an independent cohort. Collectively, this study portrays the plasma proteomic landscape of a UTUC cohort and provides a valuable resource for further biological and diagnostic research in UTUC.
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Affiliation(s)
- Yuanyuan Qu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Zhenmei Yao
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Ning Xu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Guohai Shi
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Jiaqi Su
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Shiqi Ye
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Kun Chang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Kai Li
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Yunzhi Wang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Subei Tan
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Xiaoru Pei
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Yijiao Chen
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Zhaoyu Qin
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Jinwen Feng
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Jiacheng Lv
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Jiajun Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Fahan Ma
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Shaoshuai Tang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Wenhao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Xi Tian
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Aihetaimujiang Anwaier
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Sha Tian
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Wenbo Xu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China
| | - Xinqiang Wu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Shuxuan Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Yu Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Dalong Cao
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China
| | - Menghong Sun
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China; Tissue Bank & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Hualei Gan
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China; Tissue Bank & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jianyuan Zhao
- Institute for Development and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Hailiang Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China.
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Genitourinary Cancer Institute, Shanghai 200032, China.
| | - Chen Ding
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai 200433, China.
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Zhu W, Dong X, Luo S, Guo S, Zhou W, Song W. Transcriptional activation of CSTB gene expression by transcription factor Sp3. Biochem Biophys Res Commun 2023; 649:71-78. [PMID: 36745972 DOI: 10.1016/j.bbrc.2023.01.087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023]
Abstract
CSTB has been reported to be associated with the pathogenesis of many malignant tumors, especially hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated is largely unknown. We initially cloned and analyzed the promoter region of the CSTB gene by luciferase assay and the Sp3 binding site (CCCCGCCCCGCG) was found in it. The results of electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments verified that the transcription factor, Sp3 could bind to the " CCCCGCCCCGCG ″ site of the CSTB gene promoter. We showed that the overexpression of Sp3 significantly increased the endogenous mRNA and protein expression levels of CSTB, whereas knockdown of Sp3 decreased the mRNA and protein expression levels according to quantitative real-time PCR (qRT‒PCR) and western blotting. In conclusion, CSTB gene expression is closely regulated by transcription factor Sp3, which may be a potential mechanism for the dysregulation of CSTB expression in HCC.
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Affiliation(s)
- Weiyi Zhu
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiangjun Dong
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Shuyue Luo
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Shipeng Guo
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Weihui Zhou
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
| | - Weihong Song
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, 325001, China.
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Jung CY, Kim HW, Han SH, Yoo TH, Kang SW, Park JT. Creatinine-cystatin C ratio and mortality in cancer patients: a retrospective cohort study. J Cachexia Sarcopenia Muscle 2022; 13:2064-2072. [PMID: 35478277 PMCID: PMC9397493 DOI: 10.1002/jcsm.13006] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 02/06/2022] [Accepted: 04/04/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Muscle wasting is prevalent in cancer patients, and early recognition of this phenomenon is important for risk stratification. Recent studies have suggested that the creatinine-cystatin C ratio may correlate with muscle mass in several patient populations. The association between creatinine-cystatin C ratio and survival was assessed in cancer patients. METHODS A total of 3060 patients who were evaluated for serum creatinine and cystatin C levels at the time of cancer diagnosis were included. The primary outcome was 6-month mortality. The 1-year mortality, and length of intensive care unit (ICU) and hospital stay were also evaluated. RESULTS The mean age was 61.6 ± 13.5 years, and 1409 patients (46.0%) were female. The median creatinine and cystatin C levels were 0.9 (interquartile range [IQR], 0.6-1.3) mg/dL and 1.0 (IQR, 0.8-1.5) mg/L, respectively, with a creatinine-cystatin C ratio range of 0.12-12.54. In the Cox proportional hazards analysis, an increase in the creatinine-cystatin C ratio was associated with a significant decrease in the 6-month mortality (per 1 creatinine-cystatin C ratio, hazard ratio [HR] 0.35; 95% confidence interval [CI], 0.28-0.44). When stratified into quartiles, the risk of 6-month mortality was significantly lower in the highest quartile (HR 0.30; 95% CI, 0.24-0.37) than in the lowest quartile. Analysis of 1-year mortality outcomes revealed similar findings. These associations were independent of confounding factors. The highest quartile was also associated with shorter lengths of ICU and hospital stay (both P < 0.001). CONCLUSIONS The creatinine-cystatin C ratio at the time of cancer diagnosis significantly associates with survival and hospitalization in cancer patients.
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Affiliation(s)
- Chan-Young Jung
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea
| | - Hyung Woo Kim
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea
| | - Seung Hyeok Han
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea
| | - Shin-Wook Kang
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea.,Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea
| | - Jung Tak Park
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea.,Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea
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Li Y, Zhang J, Wang B, Zhang H, He J, Wang K. Development and Validation of a Nomogram to Predict the Probability of Breast Cancer Pathologic Complete Response after Neoadjuvant Chemotherapy: A Retrospective Cohort Study. Front Surg 2022; 9:878255. [PMID: 35756481 PMCID: PMC9218360 DOI: 10.3389/fsurg.2022.878255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/20/2022] [Indexed: 12/02/2022] Open
Abstract
Background The methods used to predict the pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have some limitations. In this study, we aimed to develop a nomogram to predict breast cancer pCR after NAC based on convenient and economical multi-system hematological indicators and clinical characteristics. Materials and Methods Patients diagnosed from July 2017 to July 2019 served as the training group (N = 114), and patients diagnosed in from July 2019 to July 2021 served as the validation group (N = 102). A nomogram was developed according to eight indices, including body mass index, platelet distribution width, monocyte count, albumin, cystatin C, phosphorus, hemoglobin, and D-dimer, which were determined by multivariate logistic regression. Internal and external validation curves are used to calibrate the nomogram. Results The area under the receiver operating characteristic curve was 0.942 (95% confidence interval 0.892–0.992), and the concordance index indicated that the nomogram had good discrimination. The Hosmer–Lemeshow test and calibration curve showed that the model was well-calibrated. Conclusion The nomogram developed in this study can help clinicians accurately predict the possibility of patients achieving the pCR after NAC. This information can be used to decide the most effective treatment strategies for patients.
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Affiliation(s)
| | | | | | | | | | - Ke Wang
- Correspondence: Jianjun He Ke Wang
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Ghantous Y, Omar M, Broner EC, Agrawal N, Pearson AT, Rosenberg AJ, Mishra V, Singh A, Abu El-naaj I, Savage PA, Sidransky D, Marchionni L, Izumchenko E. A robust and interpretable gene signature for predicting the lymph node status of primary T1/T2 oral cavity squamous cell carcinoma. Int J Cancer 2022; 150:450-460. [PMID: 34569064 PMCID: PMC8760163 DOI: 10.1002/ijc.33828] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/31/2021] [Accepted: 09/21/2021] [Indexed: 02/03/2023]
Abstract
Oral cavity squamous cell carcinoma (OSCC) affects more than 30 000 individuals in the United States annually, with smoking and alcohol consumption being the main risk factors. Management of early-stage tumors usually includes surgical resection followed by postoperative radiotherapy in certain cases. The cervical lymph nodes (LNs) are the most common site for local metastasis, and elective neck dissection is usually performed if the primary tumor thickness is greater than 3.5 mm. However, postoperative histological examination often reveals that many patients with early-stage disease are negative for neck nodal metastasis, posing a pressing need for improved risk stratification to either avoid overtreatment or prevent the disease progression. To this end, we aimed to identify a primary tumor gene signature that can accurately predict cervical LN metastasis in patients with early-stage OSCC. Using gene expression profiles from 189 samples, we trained K-top scoring pairs models and identified six gene pairs that can distinguish primary tumors with nodal metastasis from those without metastasis. The signature was further validated on an independent cohort of 35 patients using real-time polymerase chain reaction (PCR) in which it achieved an area under the receiver operating characteristic (ROC) curve and accuracy of 90% and 91%, respectively. These results indicate that such signature holds promise as a quick and cost effective method for detecting patients at high risk of developing cervical LN metastasis, and may be potentially used to guide the neck treatment regimen in early-stage OSCC.
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Affiliation(s)
- Yasmin Ghantous
- Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.4 Department of Medicine, University of Chicago, Chicago, IL, USA.,Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Faculty of Medicine, Bar Ilan University, Israel
| | - Mohamed Omar
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Esther Channah Broner
- Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.4 Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Nishant Agrawal
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, IL, USA
| | - Alexander T. Pearson
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
| | - Ari J. Rosenberg
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
| | - Vasudha Mishra
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
| | - Alka Singh
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
| | - Imad Abu El-naaj
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Faculty of Medicine, Bar Ilan University, Israel
| | - Peter A. Savage
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - David Sidransky
- Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.4 Department of Medicine, University of Chicago, Chicago, IL, USA.,Corresponding Authors: Evgeny Izumchenko, Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA. , Luigi Marchionni, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. , and David Sidransky, Departments of Otolaryngology and Oncology, Johns Hopkins University, Baltimore, MD, USA
| | - Luigi Marchionni
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.,Corresponding Authors: Evgeny Izumchenko, Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA. , Luigi Marchionni, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. , and David Sidransky, Departments of Otolaryngology and Oncology, Johns Hopkins University, Baltimore, MD, USA
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.,Corresponding Authors: Evgeny Izumchenko, Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA. , Luigi Marchionni, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. , and David Sidransky, Departments of Otolaryngology and Oncology, Johns Hopkins University, Baltimore, MD, USA
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8
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Karmakar S, Purkayastha K, Dhar R, Pethusamy K, Srivastava T, Shankar A, Rath G. The issues and challenges with cancer biomarkers. J Cancer Res Ther 2022; 19:S20-S35. [PMID: 37147979 DOI: 10.4103/jcrt.jcrt_384_22] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
A biomarker is a measurable indicator used to distinguish precisely/objectively either normal biological state/pathological condition/response to a specific therapeutic intervention. The use of novel molecular biomarkers within evidence-based medicine may improve the diagnosis/treatment of disease, improve health outcomes, and reduce the disease's socio-economic impact. Presently cancer biomarkers are the backbone of therapy, with greater efficacy and better survival rates. Cancer biomarkers are extensively used to treat cancer and monitor the disease's progress, drug response, relapses, and drug resistance. The highest percent of all biomarkers explored are in the domain of cancer. Extensive research using various methods/tissues is carried out for identifying biomarkers for early detection, which has been mostly unsuccessful. The quantitative/qualitative detection of various biomarkers in different tissues should ideally be done in accordance with qualification rules laid down by the Early Detection Research Network (EDRN), Program for the Assessment of Clinical Cancer Tests (PACCT), and National Academy of Clinical Biochemistry. Many biomarkers are presently under investigation, but lacunae lie in the biomarker's sensitivity and specificity. An ideal biomarker should be quantifiable, reliable, of considerable high/low expression, correlate with the outcome progression, cost-effective, and consistent across gender and ethnic groups. Further, we also highlight that these biomarkers' application remains questionable in childhood malignancies due to the lack of reference values in the pediatric population. The development of a cancer biomarker stands very challenging due to its complexity and sensitivity/resistance to the therapy. In past decades, the cross-talks between molecular pathways have been targeted to study the nature of cancer. To generate sensitive and specific biomarkers representing the pathogenesis of specific cancer, predicting the treatment responses and outcomes would necessitate inclusion of multiple biomarkers.
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9
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Li Y, Zhang J, Wang B, Zhang H, He J, Wang K. A nomogram based on clinicopathological features and serological indicators predicting breast pathologic complete response of neoadjuvant chemotherapy in breast cancer. Sci Rep 2021; 11:11348. [PMID: 34059778 PMCID: PMC8167133 DOI: 10.1038/s41598-021-91049-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 05/17/2021] [Indexed: 02/04/2023] Open
Abstract
A single tumor marker is not enough to predict the breast pathologic complete response (bpCR) after neoadjuvant chemotherapy (NAC) in breast cancer patients. We aimed to establish a nomogram based on multiple clinicopathological features and routine serological indicators to predict bpCR after NAC in breast cancer patients. Data on clinical factors and laboratory indices of 130 breast cancer patients who underwent NAC and surgery in First Affiliated Hospital of Xi'an Jiaotong University from July 2017 to July 2019 were collected. Multivariable logistic regression analysis identified 11 independent indicators: body mass index, carbohydrate antigen 125, total protein, blood urea nitrogen, cystatin C, serum potassium, serum phosphorus, platelet distribution width, activated partial thromboplastin time, thrombin time, and hepatitis B surface antibodies. The nomogram was established based on these indicators. The 1000 bootstrap resampling internal verification calibration curve and the GiViTI calibration belt showed that the model was well calibrated. The Brier score of 0.095 indicated that the nomogram had a high accuracy. The area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.941 (95% confidence interval: 0.900-0.982) showed good discrimination of the model. In conclusion, this nomogram showed high accuracy and specificity and did not increase the economic burden of patients, thereby having a high clinical application value.
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Affiliation(s)
- Yijun Li
- grid.43169.390000 0001 0599 1243Department of Breast Surgery, First Affiliate Hospital, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061 People’s Republic of China
| | - Jian Zhang
- grid.43169.390000 0001 0599 1243Department of Breast Surgery, First Affiliate Hospital, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061 People’s Republic of China
| | - Bin Wang
- grid.43169.390000 0001 0599 1243Department of Breast Surgery, First Affiliate Hospital, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061 People’s Republic of China
| | - Huimin Zhang
- grid.43169.390000 0001 0599 1243Department of Breast Surgery, First Affiliate Hospital, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061 People’s Republic of China
| | - Jianjun He
- grid.43169.390000 0001 0599 1243Department of Breast Surgery, First Affiliate Hospital, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061 People’s Republic of China
| | - Ke Wang
- grid.43169.390000 0001 0599 1243Department of Breast Surgery, First Affiliate Hospital, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061 People’s Republic of China
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10
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Indacochea A, Guerrero S, Ureña M, Araujo F, Coll O, LLeonart ME, Gebauer F. Cold-inducible RNA binding protein promotes breast cancer cell malignancy by regulating Cystatin C levels. RNA (NEW YORK, N.Y.) 2021; 27:190-201. [PMID: 33172965 PMCID: PMC7812870 DOI: 10.1261/rna.076422.120] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 11/05/2020] [Indexed: 06/11/2023]
Abstract
Cold-inducible RNA binding protein (CIRBP) is a stress-responsive protein that promotes cancer development and inflammation. Critical to most CIRBP functions is its capacity to bind and posttranscriptionally modulate mRNA. However, a transcriptome-wide analysis of CIRBP mRNA targets in cancer has not yet been performed. Here, we use an ex vivo breast cancer model to identify CIRBP targets and mechanisms. We find that CIRBP transcript levels correlate with breast cancer subtype and are an indicator of luminal A/B prognosis. Accordingly, overexpression of CIRBP in nontumoral MCF-10A cells promotes cell growth and clonogenicity, while depletion of CIRBP from luminal A MCF-7 cells has opposite effects. We use RNA immunoprecipitation followed by high-throughput sequencing (RIP-seq) to identify a set of 204 high confident CIRBP targets in MCF-7 cells. About 10% of these showed complementary changes after CIRBP manipulation in MCF-10A and MCF-7 cells, and were highly interconnected with known breast cancer genes. To test the potential of CIRBP-mediated regulation of these targets in breast cancer development, we focused on Cystatin C (CST3), one of the most highly interconnected genes, encoding a protein that displays tumor suppressive capacities. CST3 depletion restored the effects of CIRBP depletion in MCF-7 cells, indicating that CIRBP functions, at least in part, by down-regulating CST3 levels. Our data provide a resource of CIRBP targets in breast cancer, and identify CST3 as a novel downstream mediator of CIRBP function.
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Affiliation(s)
- Alberto Indacochea
- Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Santiago Guerrero
- Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
| | - Macarena Ureña
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Ferrán Araujo
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Olga Coll
- Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
| | - Matilde E LLeonart
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
- Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Spain
| | - Fátima Gebauer
- Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
- Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
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11
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Tan XR, Huang SY, Gong S, Chen Y, Yang XJ, He QM, He SW, Liu N, Li YQ. Prognostic Value of Pretreatment Serum Cystatin C Level in Nasopharyngeal Carcinoma Patients in the Intensity-modulated Radiotherapy Era. Onco Targets Ther 2021; 14:29-37. [PMID: 33442264 PMCID: PMC7797322 DOI: 10.2147/ott.s286009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/02/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose Serum cystatin C has been considered as a significant prognostic factor for various malignancies. This study aimed to evaluate the relationship between serum cystatin C level before antitumor treatment and the prognosis of nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). Patients and Methods A cohort of 2077 NPC patients were enrolled between April 2009 and September 2012. The Kaplan–Meier curves and log rank tests were used to determine the differences of overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox regression analyses were used to determine independent prognostic factors. Results Overall, 362/2077 (17.4%) patients had high serum cystatin C level, and they were older and more male (both P<0.001), and they had higher TNM stage (all P<0.05). Kaplan–Meier analysis revealed that patients with high serum cystatin C had worse OS (P<0.001) and DFS (P<0.001). Univariate and multivariate Cox regression analysis showed that high serum cystatin C level was an independent prognostic predictor of OS (HR: 1.56, 95%CI: 1.25–1.95) and DFS (HR: 1.38, 95%CI: 1.13–1.68). Subgroup analysis based on TNM stage revealed that advanced-stage NPC patients with high serum cystatin C had poorer OS (P<0.001) and DFS (P<0.001). Conclusion Our results revealed that high serum cystatin C level before antitumor treatment can predict clinical outcomes of NPC patients treated with IMRT, and it can guide clinicians to formulate more personalized therapy for NPC patients.
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Affiliation(s)
- Xi-Rong Tan
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Sheng-Yan Huang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Sha Gong
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Yang Chen
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Xiao-Jing Yang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qing-Mei He
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Shi-Wei He
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Na Liu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Ying-Qing Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
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12
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Peng S, Yang Q, Li H, Pan Y, Wang J, Hu P, Zhang N. CTSB Knockdown Inhibits Proliferation and Tumorigenesis in HL-60 Cells. Int J Med Sci 2021; 18:1484-1491. [PMID: 33628106 PMCID: PMC7893552 DOI: 10.7150/ijms.54206] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 01/04/2021] [Indexed: 01/22/2023] Open
Abstract
Background: Cathepsin B (CTSB) was well documented in solid tumors, up-regulated of CTSB expression is linked with progression of tumors. However, the study of CTSB in adult leukemia has not been reported. Methods: Total RNA was isolated from PBMC (peripheral blood mononuclear cell) of AML patients and healthy donors. qRT-PCR was performed to detect the expression of CTSB. The association of CTSB expression with the patients' overall survival (OS) and disease-free survival (DFS) were analyzed. Stable HL-60 CTSB-shRNA cell lines were established by retrovirus infection and puromycin selection. Cell proliferation was detected by CCK-8 analysis. Tumorigenesis ability was analyzed by soft agar and xenograft nude mice model. Western blot was performed to detect the expression of CTSB and the proteins of cell signaling pathway. Results: The mRNA expression level of CTSB was up-regulated in AML patients compared to healthy control (p<0.001), and CTSB expression was significantly higher in M1, M2, M4 and M5 AML samples than healthy control. The CTSB expression in AML was associated with WBC count (p=0.037). Patients with high CTSB expression had a relatively poor OS (p=0.007) and a shorter DFS (p=0.018). Moreover, the expression level of CTSB may act as an independent prognostic factor for both OS (p=0.011) and DFS (p=0.004). Knockdown CTSB expression in HL-60 cells could inhibit the cells' proliferation and tumorigeneses in vitro and in vivo. Further study showed knockdown CTSB expression in HL-60 cells could inactive the AKT signaling pathway. Conclusions: CTSB mRNA was upregulated in AML patients. CTSB overexpression was correlated with poor prognosis and may serve as an independent prognostic factor for both OS and DFS in AML patients. Knockdown CTSB expression in HL-60 cells could inhibit the cells' proliferation and tumorigenesis. The underlying mechanism may be the inhibition of the AKT signaling pathway.
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Affiliation(s)
- Sida Peng
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, China.,Cell genetics laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, China
| | - Qingqing Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, China.,Cell genetics laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, China
| | - Huan Li
- Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000, China
| | - Yuhang Pan
- Department of Pathology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou510000, P. R. China
| | - Jiani Wang
- Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000, China
| | - Pan Hu
- Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000, China
| | - Nana Zhang
- Department of Pathology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou510000, P. R. China
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13
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Abstract
Abstract
Hen eggs are widely used, not only for human consumption, but also as an important material in food production and in pharmaceutical and cosmetics industry. Cystatin is a biologically active component of egg white, mostly used as an inhibitor of papain-like cysteine proteases. It was isolated from chicken egg white and has later been used in the nomenclature of structurally and functionally related proteins. Cystatins from animals, including mouse, rat, dog, cow and chicken egg white have been isolated and recently used in foodstuffs and drug administration. Cystatin has found its place and use in medicine due to its antimicrobial, antiviral and insecticidal effects, for the prevention of cerebral hemorrhage and control of cancer cell metastasis.
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14
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Mumtaz T, Qindeel M, Asim Ur Rehman, Tarhini M, Ahmed N, Elaissari A. Exploiting proteases for cancer theranostic through molecular imaging and drug delivery. Int J Pharm 2020; 587:119712. [PMID: 32745499 DOI: 10.1016/j.ijpharm.2020.119712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/15/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022]
Abstract
The measurement of biological processes at a molecular and cellular level serves as a basis for molecular imaging. As compared with traditional imaging approaches, molecular imaging functions to probe molecular anomalies that are the basis of a disease rather than the evaluation of end results of these molecular changes. Proteases play central role in tumor invasion, angiogenesis and metastasis thus can be exploited as a target for imaging probes in early diagnosis and treatment of tumors. Molecular imaging of protease has undergone tremendous breakthroughs in the field of diagnosis. It allows the clinicians not only to see the tumor location but also provides an insight into the expression and activity of different types of markers associated with the tumor microenvironment. These imaging techniques are expected to have a huge impact on early cancer detection and personalized cancer treatment. Effective development of protease imaging probes with the highest in vivo biocompatibility, stability and most appropriate pharmacokinetics for clinical translation will upsurge the success level of early cancer detection and treatment.
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Affiliation(s)
- Tehreem Mumtaz
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
| | - Maimoona Qindeel
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
| | - Asim Ur Rehman
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
| | - Mohamad Tarhini
- Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEPP-UMR 5007, F-69622 Lyon, France
| | - Naveed Ahmed
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
| | - Abdelhamid Elaissari
- Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEPP-UMR 5007, F-69622 Lyon, France.
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15
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Yousefi M, Dehghani S, Nosrati R, Ghanei M, Salmaninejad A, Rajaie S, Hasanzadeh M, Pasdar A. Current insights into the metastasis of epithelial ovarian cancer - hopes and hurdles. Cell Oncol (Dordr) 2020; 43:515-538. [PMID: 32418122 DOI: 10.1007/s13402-020-00513-9] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality in women worldwide. Despite various attempts to improve the diagnosis and therapy of ovarian cancer patients, the survival rate for these patients is still dismal, mainly because most of them are diagnosed at a late stage. Up to 90% of ovarian cancers arise from neoplastic transformation of ovarian surface epithelial cells, and are usually referred to as epithelial ovarian cancer (EOC). Unlike most human cancers, which are disseminated through blood-borne metastatic routes, EOC has traditionally been thought to be disseminated through direct migration of ovarian tumor cells to the peritoneal cavity and omentum via peritoneal fluid. It has recently been shown, however, that EOC can also be disseminated through blood-borne metastatic routes, challenging previous thoughts about ovarian cancer metastasis. CONCLUSIONS Here, we review our current understanding of the most updated cellular and molecular mechanisms underlying EOC metastasis and discuss in more detail two main metastatic routes of EOC, i.e., transcoelomic metastasis and hematogenous metastasis. The emerging concept of blood-borne EOC metastasis has led to exploration of the significance of circulating tumor cells (CTCs) as novel and non-invasive prognostic markers in this daunting cancer. We also evaluate the role of tumor stroma, including cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells, adipocytes, dendritic cells and extracellular matrix (ECM) components in EOC growth and metastasis. Lastly, we discuss therapeutic approaches for targeting EOC. Unraveling the mechanisms underlying EOC metastasis will open up avenues to the design of new therapeutic options. For instance, understanding the molecular mechanisms involved in the hematogenous metastasis of EOC, the biology of CTCs, and the detailed mechanisms through which EOC cells take advantage of stromal cells may help to find new opportunities for targeting EOC metastasis.
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Affiliation(s)
- Meysam Yousefi
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sadegh Dehghani
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rahim Nosrati
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Ghanei
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arash Salmaninejad
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Halal Research Center of IRI, FDA, Tehran, Iran
| | - Sara Rajaie
- Department of Biology, Islamic Azad University, Arsanjan Branch, Arsanjan, Iran
| | - Malihe Hasanzadeh
- Department of Gynecologic Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Pasdar
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran. .,Division of Applied Medicine, Faculty of Medicine, University of Aberdeen, Foresterhill, Aberdeen, UK.
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16
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Tan P, Shi M, Chen J, Xu H, Xie N, Xu H, Jiang Y, Ai JZ, Liu LR, Yang L, Wei Q. The preoperative serum cystatin-C as an independent prognostic factor for survival in upper tract urothelial carcinoma. Asian J Androl 2020; 21:163-169. [PMID: 30416134 PMCID: PMC6413544 DOI: 10.4103/aja.aja_84_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cystatin-C (Cys-C) has been reported as a valuable prognostic biomarker in various malignancies. However, its effect on upper tract urothelial carcinoma (UTUC) patients has not been investigated before. Thus, to explore the impact of Cys-C on survival outcomes in patients undergoing radical nephroureterectomy (RNU), a total of 538 patients with UTUC who underwent RNU between 2005 and 2014 in our center (West China Hospital, Chengdu, China) were included in this study. Kaplan–Meier method and Cox regression analyses were performed to assess the relationship between Cys-C and survival outcomes using SPSS version 22.0. The cutoff value of Cys-C was set as 1.4 mg l−1 using the receiver operating characteristic (ROC) curves and Youden index. The mean age of patients included was 66.1 ± 11.1 years, and the median follow-up duration was 38 (interquartile range: 19–56) months. Overall, 162 (30.1%) patients had elevated Cys-C, and they were much older and had worse renal function than those with Cys-C <1.4 mg l−1 (both P < 0.001). Meanwhile, Kaplan–Meier analysis revealed that the group with elevated Cys-C had worse cancer-specific survival (CSS, P = 0.001), disease recurrence-free survival (RFS, P = 0.003), and overall survival (OS, P < 0.001). Multivariable Cox analysis suggested that the elevated Cys-C was identified as an independent prognostic predictor of CSS (hazard ratio [HR]: 1.997, 95% confidential interval [CI]: 1.331–2.996), RFS (HR: 1.429, 95% CI: 1.009–2.023), and OS (HR: 1.989, 95% CI: 1.366–2.896). In conclusion, our result revealed that the elevated preoperative serum Cys-C was significantly associated with worse outcomes in UTUC patients undergoing RNU.
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Affiliation(s)
- Ping Tan
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ming Shi
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hang Xu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Nan Xie
- Department of Emergency, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Huan Xu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Jiang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jian-Zhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liang-Ren Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lu Yang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiang Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
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17
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PDMS-PMOXA-Nanoparticles Featuring a Cathepsin B-Triggered Release Mechanism. MATERIALS 2019; 12:ma12172836. [PMID: 31484396 PMCID: PMC6747961 DOI: 10.3390/ma12172836] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/27/2019] [Accepted: 08/30/2019] [Indexed: 12/24/2022]
Abstract
Background: It was our intention to develop cathepsin B-sensitive nanoparticles for tumor-site-directed release. These nanoparticles should be able to release their payload as close to the tumor site with a decrease of off-target effects in mind. Cathepsin B, a lysosomal cysteine protease, is associated with premalignant lesions and invasive stages of cancer. Previous studies have shown cathepsin B in lysosomes and in the extracellular matrix. Therefore, this enzyme qualifies as a trigger for such an approach. Methods: Poly(dimethylsiloxane)-b-poly(methyloxazoline) (PDMS-PMOXA) nanoparticles loaded with paclitaxel were formed by a thin-film technique and standard coupling reactions were used for surface modifications. Despite the controlled release mechanism, the physical properties of the herein created nanoparticles were described. To characterize potential in vitro model systems, quantitative polymerase chain reaction and common bioanalytical methods were employed. Conclusions: Stable paclitaxel-loaded nanoparticles with cathepsin B digestible peptide were formed and tested on the ovarian cancer cell line OVCAR-3. These nanoparticles exerted a pharmacological effect on the tumor cells suggesting a release of the payload.
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Cystatins in cancer progression: More than just cathepsin inhibitors. Biochimie 2019; 166:233-250. [PMID: 31071357 DOI: 10.1016/j.biochi.2019.05.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 05/03/2019] [Indexed: 12/20/2022]
Abstract
Cystatins are endogenous and reversible inhibitors of cysteine peptidases that are important players in cancer progression. Besides their primary role as regulators of cysteine peptidase activity, cystatins are involved in cancer development and progression through proteolysis-independent mechanisms. Mechanistic studies of cystatin function revealed that they affect all stages of cancer progression including tumor growth, apoptosis, invasion, metastasis and angiogenesis. Recently, the involvement of cystatins in the antitumor immune responses was reported. In this review, we discuss molecular mechanisms and clinical aspects of cystatins in cancer. Altered expression of cystatins in cancer resulting in harmful excessive cysteine peptidase activity has been a subject of several studies in order to find correlations with clinical outcome and therapy response. However, involvement in anti-tumor immune response and signaling cascades leading to cancer progression designates cystatins as possible targets for development of new anti-tumor drugs.
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Cogo F, Williams R, Burden RE, Scott CJ. Application of nanotechnology to target and exploit tumour associated proteases. Biochimie 2019; 166:112-131. [PMID: 31029743 DOI: 10.1016/j.biochi.2019.04.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/24/2019] [Indexed: 02/07/2023]
Abstract
Proteases are hydrolytic enzymes fundamental for a variety of physiological processes, but the loss of their regulation leads to aberrant functions that promote onset and progression of many diseases including cancer. Proteases have been implicated in almost every hallmark of cancer and whilst widely investigated for tumour therapy, clinical adoption of protease inhibitors as drugs remains a challenge due to issues such as off-target toxicity and inability to achieve therapeutic doses at the disease site. Now, nanotechnology-based solutions and strategies are emerging to circumvent these issues. In this review, preclinical advances in approaches to enhance the delivery of protease drugs and the exploitation of tumour-derived protease activities to promote targeting of nanomedicine formulations is examined. Whilst this field is still in its infancy, innovations to date suggest that nanomedicine approaches to protease targeting or inhibition may hold much therapeutic and diagnostic potential.
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Affiliation(s)
- Francesco Cogo
- Centre for Cancer Research and Cell Biology, 97 Lisburn Road, BT9 7AE, UK
| | - Rich Williams
- Centre for Cancer Research and Cell Biology, 97 Lisburn Road, BT9 7AE, UK
| | - Roberta E Burden
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, UK
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20
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Lee MK, Park JH, Gi SH, Hwang YS. Proteases are Modulated by Fascin in Oral Cancer Invasion. J Cancer Prev 2018; 23:141-146. [PMID: 30370259 PMCID: PMC6197847 DOI: 10.15430/jcp.2018.23.3.141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 09/13/2018] [Accepted: 09/19/2018] [Indexed: 11/22/2022] Open
Abstract
Background Cancer invasion is a critical factor for survival and prognosis of patients with cancer. Identifying and targeting factors that influence cancer invasion are an important strategy to overcome cancer. In this study, we investigated the role of fascin known to be associated with cancer invasion. Methods Fascin depletion was performed with lentiviral short hairpin RNA against fascin mRNA and stable cell line (Fascindep) was established. Matrigel-Transwell invasion and three-dimensional (3D) culture system were used to observe fascin depletion effects. In order to observe the changes of protease secretion by fascin depleted cancer cells, protease antibody array was performed. Results Fascin was highly expressed in invasive cancer cells. Fascin-depleted cells showed decreased cancer invasion in Matrigel-Transwell invasion and 3D culture system. In addition, inhibition of proteases secreation and decrease of intracellular proteases mRNA expression were observed in fascin deplete cells. Conclusions These results indicates that fascin is closely involved in proteases activity and cancer invasion. Therefore, fascin is a strategically important factor for controlling cancer invasion.
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Affiliation(s)
- Min Kyeong Lee
- Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Korea
| | - Ji Hyeon Park
- Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Korea
| | - Seol Hwa Gi
- Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Korea
| | - Young Sun Hwang
- Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Korea
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21
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Kwon WS, Kim TS, Nahm CH, Moon Y, Kim JJ. Aberrant cystatin-C expression in blood from patients with breast cancer is a suitable marker for monitoring tumor burden. Oncol Lett 2018; 16:5583-5590. [PMID: 30344712 PMCID: PMC6176264 DOI: 10.3892/ol.2018.9380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 03/30/2017] [Indexed: 01/05/2023] Open
Abstract
The present study was performed to evaluate the efficacy of circulating cystatin-C as a tumor monitoring biomarker at different clinical time points in patients with breast cancer over a long-term follow-up period. In addition, the secretory rate of circulating cystatin-C from cancer tissue was investigated by comparing the blood and tissue expression levels of cystatin-C. Blood samples from healthy volunteers (40 males and 40 females) were obtained at yearly health examinations if laboratory and imaging abnormalities were not detected. Blood samples from 34 patients with breast cancer were obtained at 205 different time points of clinical progression. Blood levels of cystatin-C were measured using ELISA and the tissue levels were measured using immunohistochemistry. No age-associated effect was observed in male and female blood cystatin-C levels. The positivity rate was 46% in patients (38/83) and 40% in samples collected at different time points (82/205). Blood cystatin-C levels were lowest following surgery compared with patients with systemic metastasis (P<0.001). The sensitivity, specificity and accuracy rates of ELISA were 53.6, 63.6 and 53.9%, respectively. The concordance rate between blood and tissue expression was 38%. The main reason for discordance between tissue and serum expression of cytostatin-C came from low serum positivity in samples showing tissue cytostatin-C (3/11, 27%). The specificity between cytostatin-C and CA-125 was highest in tumor absence state. In conclusion, elevated blood levels of cystatin-C were observed in 40% of breast cancer cases and were tumor-volume dependent. However, the concordance rate between tissue and blood was quite low, suggesting tumor heterogeneity of cystatin-C expression or co-acting pathway activation, such as cathepsin D. As one-third of breast cancer tissues express cystatin-C without cancer antigen 15-3 elevation, cystatin-C may represent a good tumor-monitoring marker in breast cancer.
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Affiliation(s)
- Woo Sun Kwon
- Song-Dang Institute for Cancer Research, Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Tae Soo Kim
- Song-Dang Institute for Cancer Research, Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Chung Hyun Nahm
- Department of Laboratory Medicine, Inha University College of Medicine, Incheon 22332, Republic of Korea
| | - Yeonsook Moon
- Department of Laboratory Medicine, Inha University College of Medicine, Incheon 22332, Republic of Korea
| | - Jin Ju Kim
- Department of Laboratory Medicine, Inha University College of Medicine, Incheon 22332, Republic of Korea
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22
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Liu X, Wu J, Zhang D, Bing Z, Tian J, Ni M, Zhang X, Meng Z, Liu S. Identification of Potential Key Genes Associated With the Pathogenesis and Prognosis of Gastric Cancer Based on Integrated Bioinformatics Analysis. Front Genet 2018; 9:265. [PMID: 30065754 PMCID: PMC6056647 DOI: 10.3389/fgene.2018.00265] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 07/02/2018] [Indexed: 12/23/2022] Open
Abstract
Background and Objective: Despite striking advances in multimodality management, gastric cancer (GC) remains the third cause of cancer mortality globally and identifying novel diagnostic and prognostic biomarkers is urgently demanded. The study aimed to identify potential key genes associated with the pathogenesis and prognosis of GC. Methods: Differentially expressed genes between GC and normal gastric tissue samples were screened by an integrated analysis of multiple gene expression profile datasets. Key genes related to the pathogenesis and prognosis of GC were identified by employing protein–protein interaction network and Cox proportional hazards model analyses. Results: We identified nine hub genes (TOP2A, COL1A1, COL1A2, NDC80, COL3A1, CDKN3, CEP55, TPX2, and TIMP1) which might be tightly correlated with the pathogenesis of GC. A prognostic gene signature consisted of CST2, AADAC, SERPINE1, COL8A1, SMPD3, ASPN, ITGBL1, MAP7D2, and PLEKHS1 was constructed with a good performance in predicting overall survivals. Conclusion: The findings of this study would provide some directive significance for further investigating the diagnostic and prognostic biomarkers to facilitate the molecular targeting therapy of GC.
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Affiliation(s)
- Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Dan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhitong Bing
- Evidence Based Medicine Center, School of Basic Medical Science, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jinhui Tian
- Evidence Based Medicine Center, School of Basic Medical Science, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Wagner AM, Spencer DS, Peppas NA. Advanced architectures in the design of responsive polymers for cancer nanomedicine. J Appl Polym Sci 2018; 135:46154. [PMID: 30174339 PMCID: PMC6114141 DOI: 10.1002/app.46154] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In recent decades, nanoparticles have shown significant promise as an oncology treatment modality. Responsive polymers represent a promising class of nanoparticles that can trigger delivery through the exploitation of a specific stimuli. Response to a stimulus is one of the most basic processes found in living systems. As such, the desire to engineer dynamic and functional materials is becoming more prevalent in an effort to achieve precise control over our environment. The combination of controlled radical polymerization and high yielding chemistry strategies provide an excellent basis for the development of the next generation of drug delivery systems. The versatility of polymer chemistries available enables the synthesis of increasingly complex architectures with enhanced delivery specificity and control over the desired properties to interface with biological systems. This tutorial review highlights recent developments in polymer-based approaches to internally responsive nanoparticles for oncology. Presented are concise overviews of the current challenges and opportunities in cancer nanomedicine, common polymer-based architectures, and the basis for internally triggered stimuli-response relationships commonly employed in oncology applications. Examples of the chemistry used in the design of environmentally labile nanomaterials are discussed, and we outline recent advances in creating advanced bioresponsive drug delivery architectures.
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Affiliation(s)
- Angela M Wagner
- McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, Texas 78712
| | - David S Spencer
- McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, Texas 78712
| | - Nicholas A Peppas
- McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, Texas 78712
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712
- Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712
- Department of Surgery and Perioperative Surgery, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712
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24
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Cysteine cathepsins as a prospective target for anticancer therapies-current progress and prospects. Biochimie 2018; 151:85-106. [PMID: 29870804 DOI: 10.1016/j.biochi.2018.05.023] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/31/2018] [Indexed: 02/08/2023]
Abstract
Cysteine cathepsins (CTS), being involved in both physiological and pathological processes, play an important role in the human body. During the last 30 years, it has been shown that CTS are highly upregulated in a wide variety of cancer types although they have received a little attention as a potential therapeutic target as compared to serine or metalloproteinases. Studies on the increasing problem of neoplastic progression have revealed that secretion of cell-surface- and intracellular cysteine proteases is aberrant in tumor cells and has an impact on their growth, invasion, and metastasis by taking part in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. Considering the role of CTS in carcinogenesis, inhibition of these enzymes becomes an attractive strategy for cancer therapy. The downregulation of natural CTS inhibitors (CTSsis), such as cystatins, observed in various types of cancer, supports this claim. The intention of this review is to highlight the relationship of CTS with cancer and to present illustrations that explain how some of their inhibitors affect processes related to neoplastic progression.
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25
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Leto G, Crescimanno M, Flandina C. On the role of cystatin C in cancer progression. Life Sci 2018; 202:152-160. [DOI: 10.1016/j.lfs.2018.04.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/17/2018] [Accepted: 04/11/2018] [Indexed: 02/06/2023]
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26
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Yan Y, Fan Q, Wang L, Zhou Y, Li J, Zhou K. LncRNA Snhg1, a non-degradable sponge for miR-338, promotes expression of proto-oncogene CST3 in primary esophageal cancer cells. Oncotarget 2018; 8:35750-35760. [PMID: 28423738 PMCID: PMC5482614 DOI: 10.18632/oncotarget.16189] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 02/21/2017] [Indexed: 02/03/2023] Open
Abstract
Competing endogenous RNA (ceRNA) is a newly proposed mechanism that describes a crosstalk among lncRNAs, mRNAs and their shared miRNAs. In this study, the role of miR-338-3p (miR-338) in the progression of esophageal cancer and its involve in the ceRNA regulatory circuit lncRNA-Snhg1/CST3 were explored. MiR-338 displayed a 30% decreased expression in esophageal squamous cell carcinoma tissues compared with the adjacent. Then, proto-oncogene CST3 was predicted and validated as a target gene of miR-338. Gain-and-loss-function experiments indicated that miR-338 suppressed expression of CST3 protein (also Cystatin C, CysC), promoted expression of apoptotic proteins caspase-8/3, attenuated esophageal carcinoma cell growth and induced its apoptosis. In addition, lncRNA-Snhg1 was significantly upregulated in esophageal carcinoma tissues and promoted esophageal carcinoma cell growth. Furthermore, our results from bioinformatics, luciferase reporter gene and RNA pull-down assays indicated that Snhg1 could be directly bound by miR-338. Snhg1 acted as a non-degradable sponge to relieve the suppression on CST3 caused by miR-338. In conclusion, lncRNA-Snhg1 promoted cell proliferation by acting as a non-degradable sponge for the tumor suppressor miR-338 in esophageal cancer cells.
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Affiliation(s)
- Yan Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingxia Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liping Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yue Zhou
- Department of Medical Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Li
- Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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27
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Serum Cystatin C Level Is Not a Promising Biomarker for Predicting Clinicopathological Characteristics of Bladder Urothelial Tumors. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2617439. [PMID: 29789781 PMCID: PMC5896344 DOI: 10.1155/2018/2617439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 12/28/2017] [Indexed: 01/08/2023]
Abstract
The role of cystatin C (Cys-C) in tumorigenesis and progression of bladder urothelial tumors (BUT) is still indefinite. We retrospectively collected the clinical information from the records of 425 BUT patients. Pretreatment serum Cys-C levels were compared across the various groups. Then we subgroup the patients with GFR ≥ 90 mg/min/1.73 m2, to exclude the effects of lower renal function on cystatin C. No statistically significant differences in the levels of serum Cys-C were found among the tumor characteristics (all P > 0.05). In conclusion, circulating Cys-C was not a reliable predictor for clinicopathological characteristics of BUT patients.
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28
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Pretreatment Serum Cystatin C Levels Predict Renal Function, but Not Tumor Characteristics, in Patients with Prostate Neoplasia. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7450459. [PMID: 28812020 PMCID: PMC5546082 DOI: 10.1155/2017/7450459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/10/2017] [Accepted: 06/20/2017] [Indexed: 01/08/2023]
Abstract
To evaluate the role of Cystatin C (Cys-C) in tumorigenesis and progression of prostate cancer (PCa), we retrospectively collected the clinical information from the records of 492 benign prostatic hyperplasia (BPH), 48 prostatic intraepithelial neoplasia (PIN), and 173 PCa patients, whose disease was newly diagnosed and histologically confirmed. Pretreatment serum Cys-C levels were compared across the various groups and then analyzed to identify relationships, if any, with clinical and pathological characteristics of the PCa patient group. There were no significant differences in serum Cys-C levels among the three groups (P > 0.05). In PCa patients with normal SCr levels, patient age was correlated with serum Cys-C level (P ≤ 0.001) but did not correlate with alkaline phosphatase (AKP), lactate dehydrogenase (LDH), prostate specific antigen (PSA), Gleason score, or bone metastasis status (P > 0.05). Age and SCr contributed in part to the variations in serum Cys-C levels of PCa patients (r = 0.356, P ≤ 0.001; r = 0.520, P ≤ 0.001). In conclusion, serum Cys-C levels predict renal function in patients with prostate neoplasia, but were not a biomarker for the development of prostate neoplasia, and were not correlated with the clinicopathological characteristics of PCa.
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29
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Pezhman M, Hosseini SM, Ostadhosseini S, Rouhollahi Varnosfaderani S, Sefid F, Nasr-Esfahani MH. Cathepsin B inhibitor improves developmental competency and cryo-tolerance of in vitro ovine embryos. BMC DEVELOPMENTAL BIOLOGY 2017; 17:10. [PMID: 28676034 PMCID: PMC5496377 DOI: 10.1186/s12861-017-0152-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 06/26/2017] [Indexed: 02/08/2023]
Abstract
Background Cathepsin B is a lysosomal cysteine protease involved in apoptosis and oocytes which have lower developmental competence show higher expression of Cathepsin B. Furthermore, expression of Cathepsin B show a decreasing trend from oocyte toward blastocyst stage. Results Present study assessed the effect of cathepsin B inhibitor, E-64, on developmental competency and cryo-survival of pre-implantation ovine IVF derived embryos. Cathepsin B inhibitor was added during day 3 to 8 of development. One μM E-64 was defined as the optimal concentration required for improving blastocyst rate. This concentration also reduced DNA fragmentation and BAX as apoptotic markers while increasing total cell number per blastocyst and improving anti-apoptotic marker, the BCL2. We further showed that addition of 1.0 μM of E-64 during day 3 to 8 of development improved re-expansion and hatching rates of blastocysts post vitrification. E-64 also reduced rate of DNA fragmentation and BAX expression and increased total cell number per blastocyst and BCL2 expression post vitrification. However, addition of E-64 post vitrification reduced the hatching rate. Conclusion Therefore, it can be concluded that inhibition of cathepsin B in IVC, not only improves quality and quantity of blastocysts but also improves the cryo-survival of in vitro derived blastocysts.
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Affiliation(s)
- M Pezhman
- Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Royan St., Salman St., Khorasgan, Jey St, Isfahan, 8159358686, Iran.,Department of Biology, Faculty of Science, Nour Danesh Institute of Higher Education, Isfahan, Meymeh, Iran
| | - S M Hosseini
- Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Royan St., Salman St., Khorasgan, Jey St, Isfahan, 8159358686, Iran
| | - S Ostadhosseini
- Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Royan St., Salman St., Khorasgan, Jey St, Isfahan, 8159358686, Iran
| | - Sh Rouhollahi Varnosfaderani
- Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Royan St., Salman St., Khorasgan, Jey St, Isfahan, 8159358686, Iran
| | - F Sefid
- Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Royan St., Salman St., Khorasgan, Jey St, Isfahan, 8159358686, Iran
| | - M H Nasr-Esfahani
- Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Royan St., Salman St., Khorasgan, Jey St, Isfahan, 8159358686, Iran.
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30
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Li H, Wang F, Ge S, Liu H, Yan M, Yu J. Turning Nonspecific Interference into Signal Amplification: Covalent Biosensing Nanoassembly Enabled by Metal-Catalyzed Cross-Coupling. Anal Chem 2017; 89:6834-6839. [DOI: 10.1021/acs.analchem.7b01269] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Hao Li
- Institute for Advanced
Interdisciplinary Research, University of Jinan, Jinan 250022, China
| | - Fang Wang
- Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Shenguang Ge
- Institute for Advanced
Interdisciplinary Research, University of Jinan, Jinan 250022, China
| | - Haiyun Liu
- Institute for Advanced
Interdisciplinary Research, University of Jinan, Jinan 250022, China
| | - Mei Yan
- Institute for Advanced
Interdisciplinary Research, University of Jinan, Jinan 250022, China
| | - Jinghua Yu
- Institute for Advanced
Interdisciplinary Research, University of Jinan, Jinan 250022, China
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31
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Dai DN, Li Y, Chen B, Du Y, Li SB, Lu SX, Zhao ZP, Zhou AJ, Xue N, Xia TL, Zeng MS, Zhong Q, Wei WD. Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis. J Mol Med (Berl) 2017; 95:873-886. [PMID: 28523467 PMCID: PMC5515997 DOI: 10.1007/s00109-017-1537-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 04/09/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022]
Abstract
Cystatin SN (CST1) belongs to the type 2 cystatin (CST) superfamily, which restricts the proteolytic activities of cysteine proteases. CST1 has been recently considered to be involved in the development of several human cancers. However, the prognostic significance and function of CST1 in breast cancer remains unknown. In the current study, we found that CST1 was generally upregulated in breast cancer at both mRNA and protein level. Furthermore, overall survival (OS) and disease-free survival (DFS) in the low CST1 expression subgroup were significantly superior to the high CST1 expression subgroup (OS, p < 0.001; DFS, p < 0.001), which indicated that CST1 expression level was closely correlated to the survival risk of these patients. Univariate and multivariate analyses demonstrated that CST1 expression was an independent prognostic factor, the same as ER status and nodal status. Next, CST1 overexpression promoted breast cancer cell proliferation, clonogenicity, migration, and invasion abilities. By contrast, knockdown of CST1 attenuated these malignant characteristics in breast cancer cells. Collectively, our study indicates that CST1 cannot only serve as a significant prognostic indicator but also as a potential therapeutic target for breast cancer. KEY MESSAGES High CST1 expression is negatively correlated with survival of breast cancer patients. CST1 promotes cell proliferation, clone formation, and metastasis in breast cancer cells. CST1 is a novel potential prognostic biomarker and therapeutic target for breast cancer.
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Affiliation(s)
- Da-Nian Dai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Bo Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China
| | - Yong Du
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shi-Bing Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shi-Xun Lu
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhi-Ping Zhao
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ai-Jun Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Ning Xue
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Tian-Liang Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qian Zhong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China.
| | - Wei-Dong Wei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China.
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Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells. Oncotarget 2017; 8:73793-73809. [PMID: 29088746 PMCID: PMC5650301 DOI: 10.18632/oncotarget.17379] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/22/2017] [Indexed: 01/01/2023] Open
Abstract
Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro, indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.
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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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Liu J, Zhang L, Lei J, Shen H, Ju H. Multifunctional Metal-Organic Framework Nanoprobe for Cathepsin B-Activated Cancer Cell Imaging and Chemo-Photodynamic Therapy. ACS APPLIED MATERIALS & INTERFACES 2017; 9:2150-2158. [PMID: 28033467 DOI: 10.1021/acsami.6b14446] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Integration of a photodynamic therapy platform with a drug-delivery system in a porous structure is an urgent challenge for enhanced anticancer therapy. Here, an amino-functionalized metal-organic framework (MOF), which is useful as efficient delivery vehicle for drugs and provides the -NH2 group for postsynthetic modification, is chosen and well-designed for cell imaging and chemo-photodynamic therapy. The multifunctional MOF nanoprobe was first assembled with camptothecine drug via noncovalent encapsulation and then bound with folic acid as the targeted element and chlorine e6 (Ce6)-labeled CaB substrate peptide as the recognition moiety and signal switch. The designed MOF probe can realize cathepsin B-activated cancer cell imaging and chemo-photodynamic dual-therapy combining Ce6 as the photosensitizer and the camptothecine drug. Compared with the individual treatment, the dual-functional nanoprobe presents an enhanced treatment efficiency in terms of the time of chemotherapy, laser power, and irradiation time of the photodynamic therapy, which has been confirmed in cancer cells and in vivo assays. This work presents a significant example of the MOF nanoprobe as an intracellular switch and shows great potential in cancer cell targeted imaging and multiple therapies.
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Affiliation(s)
- Jintong Liu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210023, P. R. China
| | - Lei Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210023, P. R. China
| | - Jianping Lei
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210023, P. R. China
| | - Hong Shen
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210023, P. R. China
| | - Huangxian Ju
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210023, P. R. China
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Downs LS, Lima PH, Bliss RL, Blomquist CH. Cathepsins B and D Activity and Activity Ratios in Normal Ovaries, Benign Ovarian Neoplasms, and Epithelial Ovarian Cancer. ACTA ACUST UNITED AC 2016; 12:539-44. [PMID: 16202931 DOI: 10.1016/j.jsgi.2005.06.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Cathepsins B (CB) and D (CD) belong to a family of proteases felt to be important in tumor metastasis and invasion. It has been suggested that both enzymes play a role the progression of epithelial ovarian cancer and they have been investigated as potential biomarkers for ovarian cancer. Our objective was to determine if activity ratios of these two isoforms might enhance their usefulness as biomarkers. METHODS Ovarian cancer cell lines and snap-frozen archived tissue samples were sonicated and cathepsin activities were assayed fluorometrically with cathepsin-specific peptide substrates in combination with specific inhibitors. Tissue specimens were divided into four groups: normal ovary, benign neoplasm, early-stage (I/II) cancer, and late-stage (III/IV) cancer. Median CB and CD activity and the ratio of CB to CD (CB/CD) were compared using the Wilcoxon rank sum test. Nonparametric Spearman correlation was used to determine associations between CA-125 and cathepsin activity. Logistic regression was used to test the association between cathepsin activity and malignancy. RESULTS In cell lines and tissue, CD activity remained relatively constant, while CB activity varied. CB activity was greatest in cancer tissue. Elevated serum CA-125 was associated with elevations in CB activity and CB/CD but not CD activity. Elevated CB activity and CB/CD as well as increasing CA-125 and age are all associated with malignancy. Multiple logistic regression shows that CB activity and age best predict malignancy status. CONCLUSIONS CB activity is associated with invasive ovarian neoplasm. Our results do not suggest that the ratio of activity between CB and CD provides any additional information than CB activity alone. Both tissue CB activity and CB/CD activity ratios correlate with serum levels of CA-125; however there is no correlation between CD activity and CA-125.
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Affiliation(s)
- Levi S Downs
- Department of Obstetrics, Gynecology and Women's Health, The University of Minnesota Medical School, Minneapolis, Minnesota, USA.
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Yuan J, Xu M, Li J, Li N, Chen LZ, Feng QS, Zeng YX. Prognostic value of cystatin C in patients with nasopharyngeal carcinoma: a retrospective study of 1063 patients. Clinics (Sao Paulo) 2016; 71:338-43. [PMID: 27438568 PMCID: PMC4930663 DOI: 10.6061/clinics/2016(06)09] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 03/23/2016] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE Patients with nasopharyngeal carcinoma experience highly variable outcomes despite receiving similar therapeutic regimens. Identifying biomarkers that predict survival and guide individualized therapy is urgently needed. Cystatin C has been explored as a valuable prognostic marker in several malignancies. We retrospectively assessed the relationship between serum cystatin C levels and nasopharyngeal carcinoma prognosis in a large cohort of nasopharyngeal carcinoma patients receiving long-term follow-up. METHODS A total of 1063 consecutive patients diagnosed with nasopharyngeal carcinoma from June 2006 to December 2010 were retrospectively analyzed. The serum levels of cystatin C at the time of diagnosis were collected. Receiver operating characteristic curve analysis, the Kaplan-Meier method and multivariate analyses using a Cox regression model were performed to assess the correlation of cystatin C levels with overall survival, progression-free survival, distant metastasis-free survival and loco-regional recurrence-free survival. RESULTS The median follow-up duration was 68.3 months. The optimal cut-off value of cystatin C levels for predicting death was 0.945 mg/L. Compared with the low cystatin C group, the high cystatin C group experienced significantly shorter overall survival (hazard ratio=1.47, p=0.050), progression-free survival (hazard ratio=1.65, p=0.004), distant metastasis-free survival (hazard ratio=2.37, p<0.001) and loco-regional recurrence-free survival (hazard ratio=2.40, p=0.002). Based on multivariate analysis, a high cystatin C level was identified as a significant and independent negative predictor of overall survival (hazard ratio=1.47, p=0.050), progression-free survival (hazard ratio=1.65, p=0.004), distant metastasis-free survival (hazard ratio=2.37, p<0.001), and loco-regional recurrence-free survival (hazard ratio=2.40, p=0.002). CONCLUSION Cystatin C levels are associated with the prognosis of nasopharyngeal carcinoma patients. A high cystatin C level is an independent indicator of poor prognosis for nasopharyngeal carcinoma patients.
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Affiliation(s)
- Jing Yuan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Guangzhou, Guangdong, China
- # Co-first authors
| | - Miao Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Guangzhou, Guangdong, China
- # Co-first authors
| | - Jing Li
- The First Affiliated Hospital of Zhengzhou University, Department of Medical Oncology, Zhengzhou, Henan, China
| | - Ning Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Guangzhou, Guangdong, China
| | - Li-Zhen Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Guangzhou, Guangdong, China
| | - Qi-Sheng Feng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Guangzhou, Guangdong, China
| | - Yi-Xin Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Guangzhou, Guangdong, China
- Beijing Hospital, Beijing, China
- E-mail:
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Zhang R, Yang J, Radford DC, Fang Y, Kopeček J. FRET Imaging of Enzyme-Responsive HPMA Copolymer Conjugate. Macromol Biosci 2016; 17. [PMID: 27198936 DOI: 10.1002/mabi.201600125] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 04/26/2016] [Indexed: 01/10/2023]
Abstract
Fluorescence resonance energy transfer (FRET) is applied to investigate the enzyme-responsive payload release from a macromolecular therapeutic. The donor Cy5 is attached to the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone and the acceptor Cy7 is bound to the termini of enzyme-sensitive peptide side chains. Upon exposure to an enzyme, the bond between the peptide and Cy7 is cleaved, thereby leading to the loss of FRET signal. This enzyme response is visualized at the cell, tissue and whole-body levels. The in vitro results demonstrate that high expression of cathepsin B in tumor cells induces effective release of the drug model from conjugates resulting in a high concentration of payload inside tumor cells. The in vivo and ex vivo images show that the conjugate releases drug model faster in the ovarian tumor than in the normal tissues. The information will enhance the understanding of enzyme-responsive polymer carriers and help to shape their design.
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Affiliation(s)
- Rui Zhang
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT, 84112, USA
| | - Jiyuan Yang
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT, 84112, USA
| | | | - Yixin Fang
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT, 84112, USA
| | - Jindřich Kopeček
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT, 84112, USA.,Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA
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Yang WE, Ho CC, Yang SF, Lin SH, Yeh KT, Lin CW, Chen MK. Cathepsin B Expression and the Correlation with Clinical Aspects of Oral Squamous Cell Carcinoma. PLoS One 2016; 11:e0152165. [PMID: 27031837 PMCID: PMC4816521 DOI: 10.1371/journal.pone.0152165] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 03/09/2016] [Indexed: 12/14/2022] Open
Abstract
Background Cathepsin B (CTSB), a member of the cathepsin family, is a cysteine protease that is widely distributed in the lysosomes of cells in various tissues. It is overexpressed in several human cancers and may be related to tumorigenesis. The main purpose of this study was to analyze CTSB expression in oral squamous cell carcinoma (OSCC) and its correlation with patient prognosis. Methodology/Principal Findings Tissue microarrays were used to detect CTSB expression in 280 patients and to examine the association between CTSB expression and clinicopathological parameters. In addition, the metastatic effects of the CTSB knockdown on two oral cancer cell lines were investigated by transwell migration assay. Cytoplasmic CTSB expression was detected in 34.6% (97/280) of patients. CTSB expression was correlated with positive lymph node metastasis (p = 0.007) and higher tumor grade (p = 0.008) but not with tumor size and distant metastasis. In addition, multivariate analysis using a Cox proportional hazards model revealed a higher hazard ratio, demonstrating that CTSB expression was an independent unfavorable prognostic factor in buccal mucosa carcinoma patients. Furthermore, the Kaplan–Meier curve revealed that buccal mucosa OSCC patients with positive CTSB expression had significantly shorter overall survival. Moreover, treatment with the CTSB siRNA exerted an inhibitory effect on migration in OC2 and CAL27 oral cancer cells. Conclusions We conclude that CTSB expression may be useful for determining OSCC prognosis, particularly for patients with lymph node metastasis, and may function as a biomarker of the survival of OSCC patients in Taiwan.
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Affiliation(s)
- Wei-En Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chuan-Chen Ho
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shu-Hui Lin
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Kun-Tu Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chiao-Wen Lin
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- * E-mail: (MKC); (CWL)
| | - Mu-Kuan Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
- * E-mail: (MKC); (CWL)
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Lazarides AL, Whitley MJ, Strasfeld DB, Cardona DM, Ferrer JM, Mueller JL, Fu HL, DeWitt SB, Brigman BE, Ramanujam N, Kirsch DG, Eward WC. A Fluorescence-Guided Laser Ablation System for Removal of Residual Cancer in a Mouse Model of Soft Tissue Sarcoma. Am J Cancer Res 2016; 6:155-66. [PMID: 26877775 PMCID: PMC4729765 DOI: 10.7150/thno.13536] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 09/28/2015] [Indexed: 12/22/2022] Open
Abstract
The treatment of soft tissue sarcoma (STS) generally involves tumor excision with a wide margin. Although advances in fluorescence imaging make real-time detection of cancer possible, removal is limited by the precision of the human eye and hand. Here, we describe a novel pulsed Nd:YAG laser ablation system that, when used in conjunction with a previously described molecular imaging system, can identify and ablate cancer in vivo. Mice with primary STS were injected with the protease-activatable probe LUM015 to label tumors. Resected tissues from the mice were then imaged and treated with the laser using the paired fluorescence-imaging/ laser ablation device, generating ablation clefts with sub-millimeter precision and minimal underlying tissue damage. Laser ablation was guided by fluorescence to target tumor tissues, avoiding normal structures. The selective ablation of tumor implants in vivo improved recurrence-free survival after tumor resection in a cohort of 14 mice compared to 12 mice that received no ablative therapy. This prototype system has the potential to be modified so that it can be used during surgery to improve recurrence-free survival in patients with cancer.
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Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway. Tumour Biol 2015; 37:3913-23. [DOI: 10.1007/s13277-015-4220-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 10/12/2015] [Indexed: 10/22/2022] Open
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Yang J, Zhang R, Radford DC, Kopeček J. FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy. J Control Release 2015; 218:36-44. [PMID: 26410808 DOI: 10.1016/j.jconrel.2015.09.045] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 09/17/2015] [Accepted: 09/23/2015] [Indexed: 12/22/2022]
Abstract
To develop a biodegradable polymeric drug delivery system for the treatment of ovarian cancer with the capacity for non-invasive fate monitoring, we designed and synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates. The polymer backbone was labeled with acceptor fluorophore Cy5, while donor fluorophores (Cy3 or EPI) were attached to HPMA copolymer side chains via an enzyme-cleavable GFLG linker. This design allows elucidating separately the fate of the drug and of the polymer backbone using fluorescence resonance energy transfer (FRET). The degradable diblock conjugate (2P-EPI) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization using a bifunctional chain transfer agent (Peptide2CTA). The pharmacokinetics (PK) and therapeutic effect of 2P-EPI (Mw ~100 kDa) were determined in mice bearing human ovarian carcinoma A2780 xenografts. Compared to 1st generation conjugate (P-EPI, Mw <50 kDa), 2P-EPI demonstrated remarkably improved PK such as fourfold terminal half-life (33.22 ± 3.18 h for 2P-EPI vs. 7.55 ± 3.18 h for P-EPI), which is primarily attributed to the increased molecular weight of the polymer carrier. Notably, complete tumor remission and long-term inhibition of tumorigenesis (100 days) were achieved in mice (n=5) treated with 2P-EPI. Moreover, in vitro cell uptake and intracellular drug release were determined via FRET intensity changes. The results establish a solid foundation for future in vivo tracking of drug delivery and chain scission of polymeric conjugates by FRET imaging.
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Affiliation(s)
- Jiyuan Yang
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA
| | - Rui Zhang
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA
| | | | - Jindřich Kopeček
- Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
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Monocyte-derived macrophage assisted breast cancer cell invasion as a personalized, predictive metric to score metastatic risk. Sci Rep 2015; 5:13855. [PMID: 26349896 PMCID: PMC4563359 DOI: 10.1038/srep13855] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 08/06/2015] [Indexed: 01/06/2023] Open
Abstract
Patient-to-patient variability in breast cancer progression complicates clinical treatment decisions. Of women undergoing prophylactic mastectomies, many may not have progressed to indolent forms of disease and could have benefited from milder, localized therapy. Tumor associated macrophages contribute significantly to tumor invasion and metastasis, with cysteine cathepsin proteases as important contributors. Here, a method is demonstrated by which variability in macrophage expression of cysteine cathepsins, their inhibitor cystatin C, and kinase activation can be used to train a multivariate model and score patients for invasion risk. These enzymatic profiles were used to predict macrophage-assisted MCF-7 breast cancer cell invasion in the trained computational model. To test these predictions, a priori, signals from monocytes isolated from women undergoing mastectomies were input to score their cancer invasion potential in a patient-specific manner, and successfully predicted that patient monocytes with highest predicted invasion indices matched those with more invasive initial diagnoses of the nine patients tested. Together this establishes proof-of-principle that personalized information acquired from minimally invasive blood draws may provide useful information to inform oncologists and patients of invasive/metastatic risk, helping to make decisions regarding radical mastectomy or milder, conservative treatments to save patients from hardship and surgical recovery.
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N-formylpyrazolines and N-benzoylpyrazolines as novel inhibitors of mammalian cathepsin B and cathepsin H. Bioorg Chem 2014; 57:43-50. [DOI: 10.1016/j.bioorg.2014.07.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 07/21/2014] [Accepted: 07/23/2014] [Indexed: 11/16/2022]
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Fujii T, Kamiya M, Urano Y. In Vivo Imaging of Intraperitoneally Disseminated Tumors in Model Mice by Using Activatable Fluorescent Small-Molecular Probes for Activity of Cathepsins. Bioconjug Chem 2014; 25:1838-46. [DOI: 10.1021/bc5003289] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
| | | | - Yasuteru Urano
- Basic
Research Program, Japan Science and Technology Agency, K’s Gobancho, 7, Gobancho,
Chiyoda-ku, Tokyo 102-0076, Japan
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Shi QQ, Xiang JQ, Chen L, Zhan LL, Lv XP. uPA/PAI system, cathepsin B and hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2014; 22:3941-3946. [DOI: 10.11569/wcjd.v22.i26.3941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Urokinase-type plasminogen activator and plasminogen activator inhibitor (uPA/PAI) are a pair of proteolytic enzyme activator/activator inhibitor. Cathepsin B is a lysosomal cysteine protease. It has been proved that cathepsin B can activate uPA. uPA/PAI and cathepsin B are closely related to the invasion, migration and tumor angiogenesis of malignant neoplasms. The uPA/PAI system and cathepsin B play an important role in the occurrence and development of liver cancer.
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Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Proc Natl Acad Sci U S A 2014; 111:12181-6. [PMID: 25092316 DOI: 10.1073/pnas.1406233111] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenografts. First, extensive in vitro assessment of administration sequence impact on cell cycle, viability, apoptosis, migration, and invasion revealed that treatment with paclitaxel conjugate followed by gemcitabine conjugate was the most effective scheduling strategy. Second, in an in vivo comparison with first-generation (nondegradable, molecular weight below the renal threshold) conjugates and free drugs, the second-generation degradable high-molecular weight conjugates showed distinct advantages, such as favorable pharmacokinetics (three- to five-times half-life compared with the first generation), dramatically enhanced inhibition of tumor growth (complete tumor regression) by paclitaxel and gemcitabine conjugate combination, and absence of adverse effects. In addition, multimodality imaging studies of dual-labeled model conjugates confirmed the efficacy of second-generation conjugates by visualizing more than five-times enhanced tumor accumulation, rapid conjugate internalization, and effective intracellular release of payload. Taken together, the results indicate that the second-generation degradable HPMA copolymer carrier can provide an ideal platform for the delivery of a range of antitumor compounds, which makes it one of the most attractive candidates for potential clinical application.
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Brix DM, Rafn B, Bundgaard Clemmensen K, Andersen SH, Ambartsumian N, Jäättelä M, Kallunki T. Screening and identification of small molecule inhibitors of ErbB2-induced invasion. Mol Oncol 2014; 8:1703-18. [PMID: 25070180 PMCID: PMC5528609 DOI: 10.1016/j.molonc.2014.07.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 07/04/2014] [Accepted: 07/04/2014] [Indexed: 12/11/2022] Open
Abstract
ERBB2 amplification and overexpression are strongly associated with invasive cancer with high recurrence and poor prognosis. Enhanced ErbB2 signaling induces cysteine cathepsin B and L expression leading to their higher proteolytic activity (zFRase activity), which is crucial for the invasion of ErbB2‐positive breast cancer cells in vitro. Here we introduce a simple screening system based on zFRase activity as a primary readout and a following robust invasion assay and lysosomal distribution analysis for the identification of compounds that can inhibit ErbB2‐induced invasion. With an unbiased kinase inhibitor screen, we identified Bohemine/Roscovitine, Gö6979 and JAK3 inhibitor VI as compounds that can efficiently decrease cysteine cathepsin activity. Using the well‐established and clinically relevant ErbB1 and ErbB2 inhibitor lapatinib as a positive control, we studied their ability to inhibit ErbB2‐induced invasion in 3‐dimensional Matrigel cultures. We found one of them, JAK3 inhibitor VI, capable of inhibiting invasion of highly invasive ErbB2‐positive ovarian cancer cells as efficiently as lapatinib, whereas Gö6979 and Roscovitine displayed more modest inhibition. All compounds reversed the malignant, ErbB2‐induced and invasion‐supporting peripheral distribution of lysosomes. This effect was most evident for lapatinib and JAK3 inhibitor VI and milder for Gö6979 and Roscovitine. Our results further showed that JAK3 inhibitor VI function was independent of JAK kinases but involved downregulation of cathepsin L. We postulate that the screening method and the verification experiments that are based on oncogene‐induced changes in lysosomal hydrolase activity and lysosomal distribution could be used for identification of novel inhibitors of ErbB2‐induced invasiveness. Additionally, we introduce a novel function for lapatinib in controlling malignant lysosomal distribution, that may also be involved in its capability to inhibit ErbB2‐induced invasion in vivo.
Setting up a robust screening system for identification of inhibitors of ErbB2‐induced invasion. Establishment of a 3‐dimensional model system to study invasion of ErbB2‐positive ovarian cancer cells. Identification of JAK3 inhibitor VI as a compound that efficiently abrogates ErbB2‐induced cellular invasion. Identification of lapatinib and JAK3 inhibitor VI as regulators of lysosome trafficking.
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Affiliation(s)
- D M Brix
- Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - B Rafn
- Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - K Bundgaard Clemmensen
- Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - S H Andersen
- Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - N Ambartsumian
- Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
| | - M Jäättelä
- Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - T Kallunki
- Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
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Han MS, Tung CH. Lessons learned from imaging mouse ovarian tumors: the route of probe injection makes a difference. Quant Imaging Med Surg 2014; 4:156-62. [PMID: 24914416 DOI: 10.3978/j.issn.2223-4292.2014.04.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 04/16/2014] [Indexed: 12/26/2022]
Abstract
Patients with ovarian cancer often develop small metastatic lesions in their peritoneal cavities. Fluorescent-imaging probes that can highlight these small lesions have significant value for guiding procedures and treatment decisions. In this animal study, we demonstrated that intraperitoneal (IP) delivery of a protease-sensitive fluorescent probe resulted in the labeling of all tumors regardless of their sizes with low background signals in organs. Conversely, intravenous (IV) injections of the probe resulted in high signals in most organs and large tumors (>5 mm) but not in any of the small lesions (<2 mm).
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Affiliation(s)
- Myung Shin Han
- 1 Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medical College, New York, USA ; 2 Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA ; 3 Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX, USA
| | - Ching-Hsuan Tung
- 1 Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medical College, New York, USA ; 2 Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX, USA ; 3 Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX, USA
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Davidson B, Trope CG, Reich R. The role of the tumor stroma in ovarian cancer. Front Oncol 2014; 4:104. [PMID: 24860785 PMCID: PMC4026708 DOI: 10.3389/fonc.2014.00104] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 04/27/2014] [Indexed: 01/09/2023] Open
Abstract
The tumor microenvironment, consisting of stromal myofibroblasts, endothelial cells, and leukocytes, is growingly perceived to be a major contributor to the pathogenesis and disease progression in practically all cancer types. Stromal myofibroblasts produce angiogenic factors, proteases, growth factors, immune response-modulating proteins, anti-apoptotic proteins, and signaling molecules, and express surface receptors and respond to stimuli initiated in the tumor cells to establish a bi-directional communication network in the microenvironment to promote tumor cell invasion and metastasis. Many of these molecules are candidates for targeted therapy and the cancer stroma has been recently regarded as target for biological intervention. This review provides an overview of the biology and clinical role of the stroma in ovarian cancer.
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Affiliation(s)
- Ben Davidson
- Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital , Oslo , Norway ; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine , Oslo , Norway
| | - Claes G Trope
- University of Oslo, Faculty of Medicine, Institute of Clinical Medicine , Oslo , Norway ; Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital , Oslo , Norway
| | - Reuven Reich
- Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem , Israel
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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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