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Fujii Y, Asadi Z, Mehla K. Cathepsins: Emerging targets in the tumor ecosystem to overcome cancers. Semin Cancer Biol 2025; 112:150-166. [PMID: 40228591 DOI: 10.1016/j.semcancer.2025.04.001] [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: 08/09/2024] [Revised: 03/13/2025] [Accepted: 04/07/2025] [Indexed: 04/16/2025]
Abstract
Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients' bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins' interactions, offering insights into innovative treatment strategies.
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Affiliation(s)
- Yuki Fujii
- Department of Oncology Science, University of Oklahoma Health Sciences, Oklahoma City, OK 73014, USA
| | - Zahra Asadi
- Department of Oncology Science, University of Oklahoma Health Sciences, Oklahoma City, OK 73014, USA; Department of Pathology, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
| | - Kamiya Mehla
- Department of Oncology Science, University of Oklahoma Health Sciences, Oklahoma City, OK 73014, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA.
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Liang H, Wang R, Cheng R, Ye Z, Zhao N, Zhao X, Huang Y, Jiang Z, Li W, Zheng J, Deng H, Jiang Y, Lin Y, Yan Y, Song L, Li J, Xu X, Liang W, Liu J, He J. LcProt: Proteomics-based identification of plasma biomarkers for lung cancer multievent, a multicentre study. Clin Transl Med 2025; 15:e70160. [PMID: 39783847 PMCID: PMC11714244 DOI: 10.1002/ctm2.70160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/26/2024] [Accepted: 12/18/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND Plasma protein has gained prominence in the non-invasive predicting of lung cancer. We utilised Zeolite Zotero NaY-based plasma proteomics to investigate its potential for multiple event predicting, including lung cancer diagnosis (task #1), lymph node metastasis detection (task #2) and tumour‒node‒metastasis (TNM) staging (task #3). METHODS A total of 4703 plasma proteins were quantified from 241 participants based on a prospective cohort of 2757 participants. An additional 46 participants from external prospective cohort of 735 participants were used for validation. Feature selection was performed using differential expressed protein analysis, area under curve (AUC) evaluation and least absolute shrinkage and selection operator (LASSO) regression. Random forest was used for multitask model construction based on the key proteins. Feature importance was interpreted using Shapley additive explanations (SHAP) algorithm. RESULTS For task #1, 10 proteins panel showed an AUC of .87 (.77‒.97) in the external validation. After integrating clinical factors, a significant increase diagnostic accuracy was observed with AUC of .91 (.85‒.98). For task #2, nine proteins panel achieved an AUC of .88 (.80‒.96), integration model showed an increase diagnostic accuracy with AUC of .90 (.85‒.97). For task #3, 10 proteins panel showed an AUC of .88 (.74‒.96) for stage I, .92 (.84‒.97) for stage II, .88 (.76‒.96) for stage III and .99 (.98‒.99) for stage IV in the integration model. CONCLUSIONS This study comprehensively profiled the NaY-based plasma proteome biomarker, laying the foundation for a high-performance blood test for predicting multiple events in lung cancer. KEY POINTS Our study developed an innovative nanomaterial, Zeolite NaY, which addressed the masking effect and improved the depth of the proteome. The performance of NaY-based plasma proteomics as a preclinical diagnostic tool was validated through both internal and external cohort. Furthermore, we explored the different patterns of plasma protein changes during the progression of lung cancer and used the explanations method to elucidate the roles of proteins in the multitask predictive model.
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Affiliation(s)
- Hengrui Liang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Runchen Wang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Ran Cheng
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Zhiming Ye
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Na Zhao
- Department of ProteomicsTianjin Key Laboratory of Clinical Multi‐OmicsTianjinChina
| | - Xiaohong Zhao
- Department of ProteomicsTianjin Key Laboratory of Clinical Multi‐OmicsTianjinChina
| | - Ying Huang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Zhanpeng Jiang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Wangzhong Li
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Jianqi Zheng
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Hongsheng Deng
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Yu Jiang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Yuechun Lin
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Yun Yan
- Department of ProteomicsTianjin Key Laboratory of Clinical Multi‐OmicsTianjinChina
| | - Lei Song
- Department of ProteomicsTianjin Key Laboratory of Clinical Multi‐OmicsTianjinChina
| | - Jie Li
- Department of ProteomicsTianjin Key Laboratory of Clinical Multi‐OmicsTianjinChina
| | - Xin Xu
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Wenhua Liang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Jun Liu
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
| | - Jianxing He
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseGuangzhouChina
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Saffi GT, To L, Kleine N, Melo CM, Chen K, Genc G, Lee KD, Chow JTS, Jang GH, Gallinger S, Botelho RJ, Salmena L. INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis. J Cell Biol 2024; 223:e202401012. [PMID: 39120584 PMCID: PMC11317760 DOI: 10.1083/jcb.202401012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 05/26/2024] [Accepted: 07/29/2024] [Indexed: 08/10/2024] Open
Abstract
Aggressive solid malignancies, including pancreatic ductal adenocarcinoma (PDAC), can exploit lysosomal exocytosis to modify the tumor microenvironment, enhance motility, and promote invasiveness. However, the molecular pathways through which lysosomal functions are co-opted in malignant cells remain poorly understood. In this study, we demonstrate that inositol polyphosphate 4-phosphatase, Type II (INPP4B) overexpression in PDAC is associated with PDAC progression. We show that INPP4B overexpression promotes peripheral dispersion and exocytosis of lysosomes resulting in increased migratory and invasive potential of PDAC cells. Mechanistically, INPP4B overexpression drives the generation of PtdIns(3,5)P2 on lysosomes in a PIKfyve-dependent manner, which directs TRPML-1 to trigger the release of calcium ions (Ca2+). Our findings offer a molecular understanding of the prognostic significance of INPP4B overexpression in PDAC through the discovery of a novel oncogenic signaling axis that orchestrates migratory and invasive properties of PDAC via the regulation of lysosomal phosphoinositide homeostasis.
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Affiliation(s)
- Golam T. Saffi
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Lydia To
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Nicholas Kleine
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Ché M.P. Melo
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Keyue Chen
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Gizem Genc
- Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, Canada
| | - K.C. Daniel Lee
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | | | - Gun Ho Jang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Canada
| | - Steven Gallinger
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Canada
| | - Roberto J. Botelho
- Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, Canada
| | - Leonardo Salmena
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
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Li J, Ab Rahman N, Mohamad S. Decoding Oral Carcinogenesis and Tumor Progression in Whole Cigarette Smoke Exposure: A Systematic Review. Cureus 2024; 16:e66966. [PMID: 39280415 PMCID: PMC11401675 DOI: 10.7759/cureus.66966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2024] [Indexed: 09/18/2024] Open
Abstract
This systematic review aims to highlight the molecular mechanisms by which whole cigarette smoke affects oral carcinogenesis and its progression in human oral cells, based on evidence from original research articles published in the literature. A literature search was conducted using three databases: Web of Science, Scopus, and PubMed from May to June 2024. The articles were screened, and the data were extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (2020). The included studies were subsequently evaluated using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool for bias factors. From the 14 included studies, two types of cell lines were frequently utilized: human oral mucosal epithelial cells or oral squamous cell carcinoma cells. In these cell lines, one of three forms of exposure was applied: cigarette smoke, its extract, or condensate. The mechanism of oral carcinogenesis and tumor progression includes aberrations in the heme metabolic pathway, modulation of miRNA-145, NOD1 and BiP expression, MMP-2, MMP-9, and cathepsin modulation, abnormal TSPO binding, RIP2-mediated NF-κB activation, MZF1-mediated VEGF binding, and activation of the RAGE signaling pathway. In conclusion, cigarette smoke significantly influences the development and progression of oral squamous cell carcinoma, based on the evidence highlighted in human oral cells. While previous studies have focused on specific carcinogens and pathways, this review added to our understanding of the overall impact of whole cigarette smoke on oral carcinogenesis at the molecular and cellular levels.
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Affiliation(s)
- Jiao Li
- Pathology, School of Dental Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, MYS
- Pathology, Changzhi Medical College, Shanxi, CHN
| | - Nurhayu Ab Rahman
- Oral Medicine and Oral Pathology Unit, School of Dental Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, MYS
| | - Suharni Mohamad
- Oral and Maxillofacial Diseases Research Cluster, School of Dental Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, MYS
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Paulus J, Sewald N. Small molecule- and peptide-drug conjugates addressing integrins: A story of targeted cancer treatment. J Pept Sci 2024; 30:e3561. [PMID: 38382900 DOI: 10.1002/psc.3561] [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: 09/20/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 02/23/2024]
Abstract
Targeted cancer treatment should avoid side effects and damage to healthy cells commonly encountered during traditional chemotherapy. By combining small molecule or peptidic ligands as homing devices with cytotoxic drugs connected by a cleavable or non-cleavable linker in peptide-drug conjugates (PDCs) or small molecule-drug conjugates (SMDCs), cancer cells and tumours can be selectively targeted. The development of highly affine, selective peptides and small molecules in recent years has allowed PDCs and SMDCs to increasingly compete with antibody-drug conjugates (ADCs). Integrins represent an excellent target for conjugates because they are overexpressed by most cancer cells and because of the broad knowledge about native binding partners as well as the multitude of small-molecule and peptidic ligands that have been developed over the last 30 years. In particular, integrin αVβ3 has been addressed using a variety of different PDCs and SMDCs over the last two decades, following various strategies. This review summarises and describes integrin-addressing PDCs and SMDCs while highlighting points of great interest.
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Affiliation(s)
- Jannik Paulus
- Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
| | - Norbert Sewald
- Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
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Jiang H, Dong Z, Xia X, Li X. Cathepsins in oral diseases: mechanisms and therapeutic implications. Front Immunol 2023; 14:1203071. [PMID: 37334378 PMCID: PMC10272612 DOI: 10.3389/fimmu.2023.1203071] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/18/2023] [Indexed: 06/20/2023] Open
Abstract
Cathepsins are a type of lysosomal globulin hydrolase and are crucial for many physiological processes, including the resorption of bone matrix, innate immunity, apoptosis, proliferation, metastasis, autophagy, and angiogenesis. Findings regarding their functions in human physiological processes and disorders have drawn extensive attention. In this review, we will focus on the relationship between cathepsins and oral diseases. We highlight the structural and functional properties of cathepsins related to oral diseases, as well as the regulatory mechanisms in tissue and cells and their therapeutic uses. Elucidating the associated mechanism between cathepsins and oral diseases is thought to be a promising strategy for the treatment of oral diseases and may be a starting point for further studies at the molecular level.
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Affiliation(s)
- Hao Jiang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Zuoxiang Dong
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiaomin Xia
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Xue Li
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
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Dzobo K, Dandara C. The Extracellular Matrix: Its Composition, Function, Remodeling, and Role in Tumorigenesis. Biomimetics (Basel) 2023; 8:146. [PMID: 37092398 PMCID: PMC10123695 DOI: 10.3390/biomimetics8020146] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/25/2023] Open
Abstract
The extracellular matrix (ECM) is a ubiquitous member of the body and is key to the maintenance of tissue and organ integrity. Initially thought to be a bystander in many cellular processes, the extracellular matrix has been shown to have diverse components that regulate and activate many cellular processes and ultimately influence cell phenotype. Importantly, the ECM's composition, architecture, and stiffness/elasticity influence cellular phenotypes. Under normal conditions and during development, the synthesized ECM constantly undergoes degradation and remodeling processes via the action of matrix proteases that maintain tissue homeostasis. In many pathological conditions including fibrosis and cancer, ECM synthesis, remodeling, and degradation is dysregulated, causing its integrity to be altered. Both physical and chemical cues from the ECM are sensed via receptors including integrins and play key roles in driving cellular proliferation and differentiation and in the progression of various diseases such as cancers. Advances in 'omics' technologies have seen an increase in studies focusing on bidirectional cell-matrix interactions, and here, we highlight the emerging knowledge on the role played by the ECM during normal development and in pathological conditions. This review summarizes current ECM-targeted therapies that can modify ECM tumors to overcome drug resistance and better cancer treatment.
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Affiliation(s)
- Kevin Dzobo
- Medical Research Council, SA Wound Healing Unit, Hair and Skin Research Laboratory, Division of Dermatology, Department of Medicine, Groote Schuur Hospital, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
| | - Collet Dandara
- Division of Human Genetics and Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
- The South African Medical Research Council-UCT Platform for Pharmacogenomics Research and Translation, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
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Lu L, Chen Y, Yang Z, Liang S, Zhu S, Liang X. Expression and Regulation of a Novel Decidual Cells-Derived Estrogen Target during Decidualization. Int J Mol Sci 2022; 24:ijms24010302. [PMID: 36613747 PMCID: PMC9820648 DOI: 10.3390/ijms24010302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 12/28/2022] Open
Abstract
During decidualization in rodents, uterine stromal cells undergo extensive reprogramming to differentiate into distinct cell types, forming primary decidual zones (PDZs), secondary decidual zones (SDZs), and layers of undifferentiated stromal cells. The formation of secondary decidual zones is accompanied by extensive angiogenesis. During early pregnancy, besides ovarian estrogen, de novo synthesis of estrogen in the uterus is essential for the progress of decidualization. However, the molecular mechanisms are not fully understood. Studies have shown that Cystatin B (Cstb) is highly expressed in the decidual tissue of the uterus, but the regulation and mechanism of Cstb in the process of decidualization have not been reported. Our results showed that Cstb was highly expressed in mouse decidua and artificially induced deciduoma via in situ hybridization and immunofluorescence. Estrogen stimulates the expression of Cstb through the Estrogen receptor (ER)α. Moreover, in situ synthesis of estrogen in the uterus during decidualization regulates the expression of Cstb. Silencing the expression of Cstb affects the migration ability of stromal cells. Knockdown Cstb by siRNA significantly inhibits the expression of Dtprp, a marker for mouse decidualization. Our study identifies a novel estrogen target, Cstb, during decidualization and reveals that Cstb may play a pivotal role in angiogenesis during mouse decidualization via the Angptl7.
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Zhang Y, Zhang G, Zeng Z, Pu K. Activatable molecular probes for fluorescence-guided surgery, endoscopy and tissue biopsy. Chem Soc Rev 2021; 51:566-593. [PMID: 34928283 DOI: 10.1039/d1cs00525a] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The real-time, dynamic optical visualization of lesions and margins ensures not only complete resection of the malignant tissues but also better preservation of the vital organs/tissues during surgical procedures. Most imaging probes with an "always-on" signal encounter high background noise due to their non-specific accumulation in normal tissues. By contrast, activatable molecular probes only "turn on" their signals upon reaction with the targeted biomolecules that are overexpressed in malignant cells, offering high target-to-background ratios with high specificity and sensitivity. This review summarizes the recent progress of activatable molecular probes in surgical imaging and diagnosis. The design principle and mechanism of activatable molecular probes are discussed, followed by specific emphasis on applications ranging from fluorescence-guided surgery to endoscopy and tissue biopsy. Finally, potential challenges and perspectives in the field of activatable molecular probe-enabled surgical imaging are discussed.
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Affiliation(s)
- Yan Zhang
- National Engineering Research Centre for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.,Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Guopeng Zhang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Ziling Zeng
- School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore
| | - Kanyi Pu
- School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore
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Sebzda T, Gnus J, Dziadkowiec B, Latka M, Gburek J. Diagnostic usefulness of selected proteases and acute phase factors in patients with colorectal adenocarcinoma. World J Gastroenterol 2021; 27:6673-6688. [PMID: 34754160 PMCID: PMC8554409 DOI: 10.3748/wjg.v27.i39.6673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/07/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uncontrolled growth and loss of control over basic metabolic functions, leading to invasive proliferation and metastases, are the salient traits of malignant tumors in general and colorectal cancer in particular. Invasion and metastases hinder effective tumor treatment. While surgical techniques and radiotherapy can be used to remove tumor focus, only chemotherapy can eliminate dispersed neoplastic cells. However, the efficacy of the latter method is limited in the advanced stages of the disease. Therefore, recognition of the mechanisms involved in neoplastic cell spreading is indispensable for developing effective therapies.
AIM To use a number of biomarkers involved in cancer progression and identify a panel that could be used for effective early diagnosis.
METHODS We recruited 185 patients with colorectal adenocarcinoma (98 men, 87 women with median age 63). Thirty-five healthy controls were sex and age-matched. Dukes’ staging was as follows: A = 22, B = 52, C = 72, D = 39. We analyzed patients' blood serum before surgery. We determined: (1) Cathepsin B (CB) with Barrett's method (fluorogenic substrate); (2) Leukocytic elastase (LE) in a complex with alpha 1 trypsin inhibitor (AAT) using the immunoenzymatic MERCK test; (3) Total sialic acid (TSA) with the colorimetric periodate-resorcinol method; (4) Lipid-bound sialic acid (LASA) with the colorimetric Taut's method; and (5) The antitrypsin activity (ATA) employing the colorimetric test.
RESULTS In patients, the values of the five biochemical parameters were as follows: CB = 16.1 ± 8.8 mU/L, LE = 875 ± 598 µg/L, TSA = 99 ± 31 mg%, LASA = 0.68 ± 0.33 mg%, and ATA = 3211 ± 1504 U/mL. Except for LASA, they were significantly greater than those of controls: CB = 11.4 ± 6.5 mU/L, LE = 379 ± 187 µg/L, TSA = 71.4 ± 15.1 mg%, LASA = 0.69 ± 0.28 mg%, and ATA = 2016 ± 690 U/mL. For CB and LASA, the differences between the four Dukes’ stages and controls were not statistically significant. The inter-stage differences for CB and LASA were also absent. The receiver operating characteristic (ROC) analysis revealed the potential diagnostic value of CB, TSA, and ATA. The area under ROC, sensitivity, and specificity for these three parameters were: 0.85, 72%, 90%; 0.75, 66%, 77%; and 0.77, 63%, 84%, respectively. The sensitivity and specificity for the three-parameter panel CB-TSA-ATA were equal to 88.2% and 100%, respectively.
CONCLUSION The increased value of CB, TSA, and ATA parameters are associated with tumor biology, invasion, and metastasis of colorectal cancer. The presented evidence suggests the potential value of the CB-TSA-ATA biochemical marker panel in early diagnostics.
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Affiliation(s)
- Tadeusz Sebzda
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw 50-368, Poland
| | - Jan Gnus
- Department of Physiotherapy, Wroclaw Medical University, Wroclaw 50-355, Poland
| | - Barbara Dziadkowiec
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw 50-368, Poland
| | - Miroslaw Latka
- Department of Biomedical Engineering, Wroclaw University of Science and Technology, Wroclaw 50-370, Poland
| | - Jakub Gburek
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Wroclaw 50-556, Poland
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Yang J, Ding X, Meng S, Cai J, Zhou W. The c.863A>G (p.Glu288Gly) variant of the CTSD gene is not associated with CLN10 disease. Mol Genet Genomic Med 2021; 9:e1777. [PMID: 34331747 PMCID: PMC8580076 DOI: 10.1002/mgg3.1777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 11/12/2022] Open
Abstract
Background Cathepsin D is a lysosomal aspartic protease encoded by the CTSD gene. It plays important roles in many biological processes. Biallelic loss‐of‐function mutation of CTSD is considered a cause of CLN10 disease. CLN10 is a rare autosomal recessive disorder that is one of 14 types of neuronal ceroid lipofuscinoses (NCLs). To date, only a few cases of CLN10 and 12 disease‐causing mutations have been reported worldwide. Methods Exome sequencing was performed on a 15‐year‐old girl with pervasive brain developmental disorder. The effects of the identified variants were investigated through multiple functional experiments. Results There were no differences in mRNA and protein expression, intracellular localization, maturation, and proteolytic activity between the cells with the mutant CTSD gene and those with the wild‐type CTSD gene. Conclusion These results suggest that the c.863A>G (p.Glu288Gly) homozygous variant is not a pathogenic variation, but a benign variant.
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Affiliation(s)
- Juan Yang
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoting Ding
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Shasha Meng
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jinhua Cai
- Department of Radiology of 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, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
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12
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Castration causes an increase in lysosomal size and upregulation of cathepsin D expression in principal cells along with increased secretion of procathepsin D and prosaposin oligomers in adult rat epididymis. PLoS One 2021; 16:e0250454. [PMID: 33914781 PMCID: PMC8084160 DOI: 10.1371/journal.pone.0250454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/06/2021] [Indexed: 11/19/2022] Open
Abstract
In the epididymis, lysosomal proteins of the epithelial cells are normally targeted from the Golgi apparatus to lysosomes for degradation, although their secretion into the epididymal lumen has been documented and associated with sperm maturation. In this study, cathepsin D (CatD) and prosaposin (PSAP) were examined in adult epididymis of control, and 2-day castrated rats without (Ct) and with testosterone replacement (Ct+T) to evaluate their expression and regulation within epididymal epithelial cells. By light microscope-immunocytochemistry, a quantitative increase in size of lysosomes in principal cells of Ct animals was noted from the distal initial segment to the proximal cauda. Androgen replacement did not restore the size of lysosomes to control levels. Western blot analysis revealed a significant increase in CatD expression in the epididymis of Ct animals, which suggested an upregulation of its expression in principal cells; androgens restored levels of CatD to that of controls. In contrast, PSAP expression in Ct animals was not altered from controls. Additionally, an increase in procathepsin D levels was noted from samples of the epididymal fluid of Ct compared to control animals, accompanied by an increased complex formation with PSAP. Moreover, an increased oligomerization of prosaposin was observed in the epididymal lumen of Ct rats, with changes reverted to controls in Ct+T animals. Taken together these data suggest castration causes an increased uptake of substrates that are acted upon by CatD in lysosomes of principal cells and in the lumen by procathepsin D. These substrates may be derived from apoptotic cells noted in the lumen of proximal regions and possibly by degenerating sperm in distal regions of the epididymis of Ct animals. Exploring the mechanisms by which lysosomal enzymes are synthesized and secreted by the epididymis may help resolve some of the issues originating from epididymal dysfunctions with relevance to sperm maturation.
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13
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Jeger JL. Endosomes, lysosomes, and the role of endosomal and lysosomal biogenesis in cancer development. Mol Biol Rep 2020; 47:9801-9810. [PMID: 33185829 DOI: 10.1007/s11033-020-05993-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/19/2022]
Abstract
Endosomes and lysosomes are membrane-bound organelles crucial for the normal functioning of the eukaryotic cell. The primary function of endosomes relates to the transportation of extracellular material into the intracellular domain. Lysosomes, on the other hand, are primarily involved in the degradation of macromolecules. Endosomes and lysosomes interact through two distinct pathways: kiss-and-run and direct fusion. In addition to the internalization of particles, endosomes also play an important role in cell signaling and autophagy. Disruptions in either of these processes may contribute to cancer development. Lysosomal proteins, such as cathepsins, can play a role in both tumorigenesis and cancer cell apoptosis. Since endosomal and lysosomal biogenesis and signaling are important components of normal cellular growth and proliferation, proteins involved in these processes are attractive targets for cancer research and, potentially, therapeutics. This literature review provides an overview of the endocytic pathway, endolysosome formation, and the interplay between endosomal/lysosomal biogenesis and carcinogenesis.
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14
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Yang H, Zhang R, Zhang Y, Liu Q, Li Y, Gong J, Hou Y. Cathepsin-L is involved in degradation of fat body and programmed cell death in Bombyx mori. Gene 2020; 760:144998. [DOI: 10.1016/j.gene.2020.144998] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 12/25/2022]
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15
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Medoro A, Bartollino S, Mignogna D, Marziliano N, Porcile C, Nizzari M, Florio T, Pagano A, Raimo G, Intrieri M, Russo C. Proteases Upregulation in Sporadic Alzheimer's Disease Brain. J Alzheimers Dis 2020; 68:931-938. [PMID: 30814362 DOI: 10.3233/jad-181284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Certain proteases are involved in Alzheimer's disease (AD) and their erroneous control may contribute to the pathology onset and progression. In this study we evaluated the cerebral expression of eight proteases, involved in both AβPP processing and extracellular matrix remodeling. Among these proteases, ADAM10, ADAMTS1, Cathepsin D, and Meprin β show a significantly higher mRNAs expression in sporadic AD subjects versus controls, while ADAMTS1, Cathepsin D, and Meprin β show an increment also at the protein level. These data indicate that transcriptional events affecting brain proteases are activated in AD patients, suggesting a link between proteolysis and AD.
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Affiliation(s)
- Alessandro Medoro
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Silvia Bartollino
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Donatella Mignogna
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Nicola Marziliano
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy.,Clinical Pathology Laboratory, ASL Taranto, Italy
| | - Carola Porcile
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Mario Nizzari
- Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genova, Genova, Italy
| | - Tullio Florio
- Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genova, Genova, Italy.,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Aldo Pagano
- Department of Experimental Medicine, University of Genova, Genova, Italy.,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Gennaro Raimo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Mariano Intrieri
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Claudio Russo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
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16
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Geiger M, Stubenrauch KG, Sam J, Richter WF, Jordan G, Eckmann J, Hage C, Nicolini V, Freimoser-Grundschober A, Ritter M, Lauer ME, Stahlberg H, Ringler P, Patel J, Sullivan E, Grau-Richards S, Endres S, Kobold S, Umaña P, Brünker P, Klein C. Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody. Nat Commun 2020; 11:3196. [PMID: 32581215 PMCID: PMC7314773 DOI: 10.1038/s41467-020-16838-w] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/29/2020] [Indexed: 01/06/2023] Open
Abstract
T-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce tumor cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe a protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected to the anti-CD3 Fab through a tumor protease-cleavable linker. The potency of this Prot- FOLR1-TCB is recovered following protease-cleavage of the linker releasing the anti-idiotypic anti-CD3 scFv. In vivo, the Prot-FOLR1-TCB mediates antitumor efficacy comparable to the parental FOLR1-TCB whereas a noncleavable control Prot-FOLR1-TCB is inactive. In contrast, killing of bronchial epithelial and renal cortical cells with low FOLR1 expression is prevented compared to the parental FOLR1-TCB. The findings are confirmed for mesothelin as alternative tumor antigen. Thus, masking the anti-CD3 Fab fragment with an anti-idiotypic mask and cleavage of the mask by tumor-specific proteases can be applied to enhance specificity and safety of TCBs.
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Grants
- SK is supported by grants from the Wilhelm Sander Stiftung (grant number 2014.018.1 to SE and SK), the international doctoral program “i-Target: Immunotargeting of cancer” funded by the Elite Network of Bavaria (to SK and SE), the Melanoma Research Alliance (grant number N269626 to SE and 409510 to SK), the Marie-Sklodowska-Curie “Training Network for the Immunotherapy of Cancer (IMMUTRAIN)” funded by the H2020 program of the European Union (to SE and SK), by LMU Munich‘s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to SE and SK), the Bundesministerium für Bildung und Forschung (project Oncoattract to SE and SK).
- SK and SE are supported by grants from the Wilhelm Sander Stiftung (grant number 2014.018.1 to SE and SK), the international doctoral program “i-Target: Immunotargeting of cancer” funded by the Elite Network of Bavaria (to SK and SE), the Melanoma Research Alliance (grant number N269626 to SE and 409510 to SK), the Marie-Sklodowska-Curie “Training Network for the Immunotherapy of Cancer (IMMUTRAIN)” funded by the H2020 program of the European Union (to SE and SK), the Else Kröner- Fresenius-Stiftung (to SK), the German Cancer Aid (to SK), the Ernst-Jung-Stiftung (to SK), by LMU Munich‘s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to SE and SK), the Bundesministerium für Bildung und Forschung (project Oncoattract to SE and SK), the Deutsche Forschungsgemeinschaft, the José-Carreras Leukämie Stiftung, the Hector-Foundation (all to SK) and the European Research Council (ERC, grant 756017, ARMOR-T to SK).
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Affiliation(s)
- Martina Geiger
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Lindwurmstraße 2a, Member of the German Center for Lung Research (DZL), 80337, Munich, Germany
| | - Kay-Gunnar Stubenrauch
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany
| | - Johannes Sam
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
| | - Wolfgang F Richter
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Gregor Jordan
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany
| | - Jan Eckmann
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany
| | - Carina Hage
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany
| | - Valeria Nicolini
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
| | - Anne Freimoser-Grundschober
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
| | - Mirko Ritter
- Roche Diagnostics, CPS Research and Development, Nonnenwald 2, 82372, Penzberg, Germany
| | - Matthias E Lauer
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Henning Stahlberg
- Center for Cellular Imaging and Nano Analytics, Biozentrum, University of Basel, 4070, Basel, Switzerland
| | - Philippe Ringler
- Center for Cellular Imaging and Nano Analytics, Biozentrum, University of Basel, 4070, Basel, Switzerland
| | - Jigar Patel
- Roche Sequencing, NimbleGen, Madison, WI, 53719, USA
- Nimble Therapeutics Inc., 500S Rosa Rd, Madison, WI, 53719, USA
| | - Eric Sullivan
- Roche Sequencing, NimbleGen, Madison, WI, 53719, USA
- Nimble Therapeutics Inc., 500S Rosa Rd, Madison, WI, 53719, USA
| | - Sandra Grau-Richards
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
| | - Stefan Endres
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Lindwurmstraße 2a, Member of the German Center for Lung Research (DZL), 80337, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, Munich, Germany
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Lindwurmstraße 2a, Member of the German Center for Lung Research (DZL), 80337, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, Munich, Germany
| | - Pablo Umaña
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
| | - Peter Brünker
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland
| | - Christian Klein
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
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17
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Pouliquen DL, Boissard A, Coqueret O, Guette C. Biomarkers of tumor invasiveness in proteomics (Review). Int J Oncol 2020; 57:409-432. [PMID: 32468071 PMCID: PMC7307599 DOI: 10.3892/ijo.2020.5075] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/07/2020] [Indexed: 12/13/2022] Open
Abstract
Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of references involving studies on the cancer metastatic process has doubled since 2010, while the last 5 years have seen the development of novel technologies combining deep proteome coverage capabilities with quantitative consistency and accuracy. To highlight key findings within this huge amount of information, the present review identified a list of tumor invasive biomarkers based on both the literature and data collected on a biocollection of experimental cell lines, tumor models of increasing invasiveness and tumor samples from patients with colorectal or breast cancer. Crossing these different data sources led to 76 proteins of interest out of 1,245 mentioned in the literature. Information on these proteins can potentially be translated into clinical prospects, since they represent potential targets for the development and evaluation of innovative therapies, alone or in combination. Herein, a systematical review of the biology of each of these proteins, including their specific subcellular/extracellular or multiple localizations is presented. Finally, as an important advantage of quantitative proteomics is the ability to provide data on all these molecules simultaneously in cell pellets, body fluids or paraffin‑embedded sections of tumors/invaded tissues, the significance of some of their interconnections is discussed.
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Affiliation(s)
| | - Alice Boissard
- Paul Papin ICO Cancer Center, CRCINA, Inserm, Université d'Angers, F‑44000 Nantes, France
| | | | - Catherine Guette
- Paul Papin ICO Cancer Center, CRCINA, Inserm, Université d'Angers, F‑44000 Nantes, France
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18
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Reithmeier A, Norgård M, Ek-Rylander B, Näreoja T, Andersson G. Cathepsin K regulates localization and secretion of Tartrate-Resistant Acid Phosphatase (TRAP) in TRAP-overexpressing MDA-MB-231 breast cancer cells. BMC Mol Cell Biol 2020; 21:15. [PMID: 32188406 PMCID: PMC7081696 DOI: 10.1186/s12860-020-00253-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 02/17/2020] [Indexed: 11/30/2022] Open
Abstract
Background Tartrate–resistant acid phosphatase (TRAP/ ACP5) belongs to the binuclear metallophosphatase family and is present in two isoforms. The primary translation product is an uncleaved TRAP 5a isoform with low phosphatase activity. TRAP 5a can be post-translationally processed to a cleaved TRAP 5b isoform with high phosphatase activity by e.g. cysteine proteinases, such as Cathepsin K (CtsK). The relevance of the phosphatase activity of TRAP 5b has been demonstrated for proliferation, migration and invasion of cancer cells. TRAP-overexpressing MDA-MB-231 breast cancer cells displayed higher levels of TRAP 5a and efficient processing of TRAP 5a to TRAP 5b protein, but no changes in levels of CtsK when compared to mock-transfected cells. In TRAP-overexpressing cells colocalization of TRAP 5a and proCtsK was augmented, providing a plausible mechanism for generation of TRAP 5b. CtsK expression has been associated with cancer progression and has been pharmacologically targeted in several clinical studies. Results In the current study, CtsK inhibition with MK-0822/Odanacatib did not abrogate the formation of TRAP 5b, but reversibly increased the intracellular levels of a N-terminal fragment of TRAP 5b and reduced secretion of TRAP 5a reversibly. However, MK-0822 treatment neither altered intracellular TRAP activity nor TRAP-dependent cell migration, suggesting involvement of additional proteases in proteolytic processing of TRAP 5a. Notwithstanding, CtsK was shown to be colocalized with TRAP and to be involved in the regulation of secretion of TRAP 5a in a breast cancer cell line, while it still was not essential for processing of TRAP 5a to TRAP 5b isoform. Conclusion In cancer cells multiple proteases are involved in cleaving TRAP 5a to high-activity phosphatase TRAP 5b. However, CtsK-inhibiting treatment was able to reduce secretion TRAP 5a from TRAP-overexpressing cancer cells.
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Affiliation(s)
- Anja Reithmeier
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Alfred Nobels allé 8, 141 52, Stockholm, Sweden. .,Present Address: Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Tomtebodavägen 23A, 171 65, Solna, Sweden.
| | - Maria Norgård
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Alfred Nobels allé 8, 141 52, Stockholm, Sweden
| | - Barbro Ek-Rylander
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Alfred Nobels allé 8, 141 52, Stockholm, Sweden
| | - Tuomas Näreoja
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Alfred Nobels allé 8, 141 52, Stockholm, Sweden.
| | - Göran Andersson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Alfred Nobels allé 8, 141 52, Stockholm, Sweden
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19
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Mohtar MA, Syafruddin SE, Nasir SN, Yew LT. Revisiting the Roles of Pro-Metastatic EpCAM in Cancer. Biomolecules 2020; 10:biom10020255. [PMID: 32046162 PMCID: PMC7072682 DOI: 10.3390/biom10020255] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 12/12/2022] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is expressed at basal levels in the basolateral membrane of normal epithelial cells. However, EpCAM expression is upregulated in solid epithelial cancers and stem cells. EpCAM can also be found in disseminated tumour cells and circulating tumour cells. Various OMICs studies have demonstrated that EpCAM plays roles in several key biological processes such as cell adhesion, migration, proliferation and differentiation. Additionally, EpCAM can be detected in the bodily fluid of cancer patients suggesting that EpCAM is a pathophysiologically relevant anti-tumour target as well as being utilized as a diagnostic/prognostic agent for a variety of cancers. This review will focus on the structure-features of EpCAM protein and discuss recent evidence on the pathological and physiological roles of EpCAM in modulating cell adhesion and signalling pathways in cancers as well as deliberating the clinical implication of EpCAM as a therapeutic target.
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20
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Kilar E, Siewiński M, Hirnle L, Skiba T, Goła B K, Gburek J, Murawski M, Janocha A. Differences in cysteine peptidases-like activity in sera of patients with breast cancer. Cancer Biomark 2019; 27:335-341. [PMID: 31683457 DOI: 10.3233/cbm-190327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The key role in carcinogenesis with destruction of the extracellular matrix is played by proteases released by invasive cancer cells. Cysteine peptidases, such as cathepsin B and L, take an important role in cancer progression and metastasis. OBJECTIVES Cysteine peptidase-like activity (CPA) in sera of patients with breast cancer at different stages of disease and the influence of genetic predisposition associated with BRCA-1 gene mutations were analysed. METHODS CPA in serum was determined with the spectrofluorometric technique using Z-Phe-Arg-AMC as a substrate. Determination was carried out in 111 breast cancer patients in comparison to a control group of 50 healthy subjects. RESULTS The highest CPA was found in breast cancer patients with a hereditary predisposition bearing BRCA1 gene mutations, and the lowest activity was found in patients who had a tumour surgically removed and before adjuvant therapy. The differences in the activities between control group and cancer groups were statistically significant (p< 0.05), except from group of cancer patients in complete remission (p< 0.52). CONCLUSIONS Serum CPA in patients with breast cancer differs depending on the cancer stage and treatment methods. Our study demonstrate the correlation between BRCA-1 gene mutations and the increased level of CPA.
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Affiliation(s)
- Ewa Kilar
- Department of Oncology, District Hospital, Swidnica, Poland
| | - Maciej Siewiński
- Department of Basic Sciences, Wroclaw Medical University, Wroclaw, Poland
| | - Lidia Hirnle
- 1st Department and Clinic of Gynaecology and Obstetrics, Wrocław Medical University, Wroclaw, Poland
| | - Teresa Skiba
- Department of Animal Product Technology and Quality Management, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | - Krzysztof Goła B
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Jakub Gburek
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Marek Murawski
- 1st Department and Clinic of Gynaecology and Obstetrics, Wrocław Medical University, Wroclaw, Poland
| | - Anna Janocha
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw, Poland
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21
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Ma Y, Dela Cruz-Chuh J, Khojasteh SC, Dragovich PS, Pillow TH, Zhang D. Carfilzomib Is Not an Appropriate Payload of Antibody-Drug Conjugates Due to Rapid Inactivation by Lysosomal Enzymes. Drug Metab Dispos 2019; 47:884-889. [PMID: 31072822 DOI: 10.1124/dmd.119.086595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 04/29/2019] [Indexed: 11/22/2022] Open
Abstract
Carfilzomib (CFZ) is a proteasome inhibitor used for oncology indications including treating multiple myeloma. CFZ is a potent cytotoxic agent with an IC50 value in the nanomolar range in various cancer cell lines and was considered as a potential payload for antibody drug conjugates (ADCs); however, the conjugated CFZ to anti-CD22 or anti-HER2 antibody totally abolishes the in vitro potency. This was a surprise since with other payloads such as monomethyl auristatin E (MMAE), where potent antiproliferation efficacy was retained as MMAE alone or as a payload in an ADC. Further investigations were conducted using CFZ alone, CFZ with a linker, and CFZ-ADC with tissue matrices including lysosomal enzymes. With CFZ linked to the ADC, cathepsin B (a lysosomal enzyme) was efficient in liberating CFZ from the ADC by cleavage of the valine-citrulline linker. At the same time, the liberated CFZ in the lysosome was inactivated due to further metabolism by lysosomal enzymes. The products from epoxide and amide hydrolysis were identified from these incubations. These results suggested that the CFZ-ADC upon uptake and internalization specifically delivers CFZ payload to the lysosomes, where CFZ was inactivated. On the other hand, CFZ by itself is not as vulnerable and could reach its target. Therefore, lysosomal stability is an important criterion in the selection of a payload for making the next generation of potent ADC therapeutics.
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Affiliation(s)
- Yong Ma
- Drug Metabolism and Disposition (Y.M., S.C.K., D.Z.), Biochemical and Cellular Pharmacology (J.D.C.-C.), and Discovery Chemistry (P.S.D., T.H.P.), Genentech, South San Francisco, California
| | - Josefa Dela Cruz-Chuh
- Drug Metabolism and Disposition (Y.M., S.C.K., D.Z.), Biochemical and Cellular Pharmacology (J.D.C.-C.), and Discovery Chemistry (P.S.D., T.H.P.), Genentech, South San Francisco, California
| | - S Cyrus Khojasteh
- Drug Metabolism and Disposition (Y.M., S.C.K., D.Z.), Biochemical and Cellular Pharmacology (J.D.C.-C.), and Discovery Chemistry (P.S.D., T.H.P.), Genentech, South San Francisco, California
| | - Peter S Dragovich
- Drug Metabolism and Disposition (Y.M., S.C.K., D.Z.), Biochemical and Cellular Pharmacology (J.D.C.-C.), and Discovery Chemistry (P.S.D., T.H.P.), Genentech, South San Francisco, California
| | - Thomas H Pillow
- Drug Metabolism and Disposition (Y.M., S.C.K., D.Z.), Biochemical and Cellular Pharmacology (J.D.C.-C.), and Discovery Chemistry (P.S.D., T.H.P.), Genentech, South San Francisco, California
| | - Donglu Zhang
- Drug Metabolism and Disposition (Y.M., S.C.K., D.Z.), Biochemical and Cellular Pharmacology (J.D.C.-C.), and Discovery Chemistry (P.S.D., T.H.P.), Genentech, South San Francisco, California
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22
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Shockey WA, Kieslich CA, Wilder CL, Watson V, Platt MO. Dynamic Model of Protease State and Inhibitor Trafficking to Predict Protease Activity in Breast Cancer Cells. Cell Mol Bioeng 2019; 12:275-288. [PMID: 31719914 DOI: 10.1007/s12195-019-00580-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 06/10/2019] [Indexed: 11/25/2022] Open
Abstract
Introduction Cysteine cathepsins are implicated in breast cancer progression, produced by both transformed epithelial cells and infiltrated stromal cells in tumors, but to date, no cathepsin inhibitor has been approved for clinical use due to unexpected side effects. This study explores cellular feedback to cathepsin inhibitors that might yield non-intuitive responses, and uses computational models to determine underlying cathepsin-inhibitor dynamics. Methods MDA-MB-231 cells treated with E64 were tested by multiplex cathepsin zymography and immunoblotting to quantify total, active, and inactive cathepsins S and L. This data was used to parameterize mathematical models of intracellular free and inhibited cathepsins, and then applied to a dynamic model predicting cathepsin responses to other classes of cathepsin inhibitors that have also failed clinical trials. Results E64 treated cells exhibited increased amounts of active cathepsin S and reduced amount of active cathepsin L, although E64 binds tightly to both. This inhibitor response was not unique to cancer cells or any one cell type, suggesting an underlying fundamental mechanism of E64 preserving activity of cathepsin S, but not cathepsin L. Computational models were able to predict and differentiate between inhibitor-bound, active, and inactive cathepsin species and demonstrate how different classes of cathepsin inhibitors can have drastically divergent effects on active cathepsins located in different intracellular compartments. Conclusions Together, this work has important implications for the development of mathematical model systems for protease inhibition in tissue destructive diseases, and consideration of preservation mechanisms by inhibitors that could alter perceived benefits of these treatment modalities.
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Affiliation(s)
- W Andrew Shockey
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology & Emory University, 950 Atlantic Drive, Suite 3015, Atlanta, GA 30332 USA
| | - Christopher A Kieslich
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology & Emory University, 950 Atlantic Drive, Suite 3015, Atlanta, GA 30332 USA
| | - Catera L Wilder
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology & Emory University, 950 Atlantic Drive, Suite 3015, Atlanta, GA 30332 USA
| | - Valencia Watson
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology & Emory University, 950 Atlantic Drive, Suite 3015, Atlanta, GA 30332 USA
| | - Manu O Platt
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology & Emory University, 950 Atlantic Drive, Suite 3015, Atlanta, GA 30332 USA
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Patil S, Babu N, Subbannayya T, Mohan S, Sathe G, Solanki H, Rajagopalan P, Patel K, Advani J, Bhandi S, Sidransky D, Chatterjee A, Gowda H, Ferrari M. Secretome analysis of oral keratinocytes chronically exposed to shisha. Cancer Biomark 2019; 25:29-41. [PMID: 31033461 DOI: 10.3233/cbm-182099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Shankargouda Patil
- Department of Medical Biotechnologies, School of Dental Medicine, University of Siena, Siena, Italy
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
- Department of Medical Biotechnologies, School of Dental Medicine, University of Siena, Siena, Italy
| | - Niraj Babu
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
- Department of Medical Biotechnologies, School of Dental Medicine, University of Siena, Siena, Italy
| | | | - Sonali V. Mohan
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Hitendra S. Solanki
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | | | - Krishna Patel
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Jayshree Advani
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Shilpa Bhandi
- Department of Restorative Dental Sciences, Division of Operative Dentistry, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - David Sidransky
- Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Marco Ferrari
- Department of Medical Biotechnologies, School of Dental Medicine, University of Siena, Siena, Italy
- Department of Restorative Dentistry, School of Dentistry, University of Leeds, Leeds, UK
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24
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Henderson VM, Hawsawi O, Burton LJ, Campbell T, Trice K, Dougan J, Howard SM, Odero-Marah VA. Cancer-bone microenvironmental interactions promotes STAT3 signaling. Mol Carcinog 2019; 58:1349-1361. [PMID: 31045290 DOI: 10.1002/mc.23019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 03/22/2019] [Accepted: 03/29/2019] [Indexed: 12/30/2022]
Abstract
Prostate cancer (PCa) patients' mortality is mainly attributed to complications caused by metastasis of the tumor cells to organs critical for survival, such as bone. We hypothesized that PCa cell-bone interactions would promote paracrine signaling. A panel of PCa cell lines were cocultured with hydroxyapatite ([HA]; inorganic component of bone) of different densities. Conditioned media (CM) was collected and analyzed for calcium levels and effect on paracrine signaling, cell migration, and viability in vitro and in vivo. Our results showed that calcium levels were elevated in CM from cancer cell-bone cocultures, compared to media or cancer cells alone, and this could be antagonized by ethylene glycol-bis(2-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA), a calcium chelator, or knockdown of Snail protein. We also observed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation and paracrine cell proliferation and migration in LNCaP cells incubated with CM from various cell lines; this phosphorylation and cell migration could be antagonized by Snail knockdown or various inhibitors including EGTA, STAT3 inhibitor (WP1066) or cathepsin L inhibitor (Z-FY-CHO). In vivo, higher HA bone density increased tumorigenicity and migration of tumor cells to HA implant. Our study shows that cancer-bone microenvironment interactions lead to calcium-STAT3 signaling, which may present an area for therapeutic targeting of metastatic PCa.
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Affiliation(s)
- Veronica M Henderson
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Ohuod Hawsawi
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Liza J Burton
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Taaliah Campbell
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Kennedi Trice
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Jodi Dougan
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Simone M Howard
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Valerie A Odero-Marah
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
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25
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Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and metastasis-inhibiting effects on breast cancer cells. Bioorg Chem 2019; 84:239-253. [DOI: 10.1016/j.bioorg.2018.11.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/05/2018] [Accepted: 11/17/2018] [Indexed: 11/17/2022]
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26
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Nakamura N, Watanabe H, Okamura K, Kagami S. Assessment of renal function in Japanese children with malignancies using serum cystatin C. THE JOURNAL OF MEDICAL INVESTIGATION 2018; 65:231-235. [PMID: 30282866 DOI: 10.2152/jmi.65.231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Several factors besides renal function influence serum cystatin C (CysC) levels. The present study evaluates the value of serum CysC and the equation for CysC based estimated glomerular filtration rate (CysC-eGFR) for Japanese children with malignancies. We collected information at 36 time points from 13 patients aged ≤ 17 years with malignancies. We assessed tumor activity, cell recovery phase after chemotherapy, neutropenia phase, inflammation response and medication with granulocyte-colony stimulating factor, steroid, and levothyroxine as risk factors associated with serum CysC levels. Although no 24-h creatinine clearance (CCr) data collected at 36 time points indicated renal dysfunction, serum CysC levels were above and below the reference values at four and five time points, respectively. The frequency of elevated serum CysC levels was higher in patients without therapy or with stable or progressive disease than among those with a complete or partial response (p = 0.0046). The correlation coefficient between CCr and CysC-eGFR was 0.355 (p = 0.054), but this improved to 0.663 (p = 0.0010) when restricted to patients with a complete or partial response. Levels of serum CysC might become elevated regardless of renal function, and CysC-eGFR might become unpredictable during the active phase of tumors. J. Med. Invest. 65:231-235, August, 2018.
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Affiliation(s)
- Nami Nakamura
- Department of Pediatrics, the University of Tokushima Graduate School.,Department of Pediatrics, The Tsurugi Town Handa Hospital
| | | | - Kazumi Okamura
- Department of Pediatrics, the University of Tokushima Graduate School
| | - Shoji Kagami
- Department of Pediatrics, the University of Tokushima Graduate School
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de Novais LMR, de Arueira CCO, Ferreira LF, Ribeiro TAN, Sousa PT, Jacinto MJ, de Carvalho MG, Judice WAS, Jesus LOP, de Souza AA, Torquato HFV, Paredes-Gamero EJ, Silva VC. 4'-Hydroxy-6,7-methylenedioxy-3-methoxyflavone: A novel flavonoid from Dulacia egleri with potential inhibitory activity against cathepsins B and L. Fitoterapia 2018; 132:26-29. [PMID: 30114470 DOI: 10.1016/j.fitote.2018.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 08/08/2018] [Accepted: 08/12/2018] [Indexed: 11/27/2022]
Abstract
A new flavone, 4'-hydroxy-6,7-methylenedioxy-3-methoxyflavone 1, and two other nucleosides, ribavirin 2 and adenosine 3, were isolated from the leaves of Dulacia egleri. The nucleosides were identified by spectroscopic techniques (1D, 2D-NMR) while the structure of the flavonoid was established by 1D, 2D-NMR analysis, including HRESIMS data. The results obtained in the biological assays showed that the compound 1 was able to inhibit cathepsins B and L with IC50 of 14.88 ± 0.18 μM and 3.19 ± 0.07 μM, respectively. The mechanism of inhibition for both enzymes were determined showing to be competitive at cathepsin B with Ki = 12.8 ± 0.6 μM and non-linear non-competitive with positive cooperativity inhibition at cathepsin L with Ki = 322 ± 33 μM, αKi = 133 ± 15 μM, βKi = 5.14 ± 0.41 μM and γKi = 13.2 ± 13 μM.
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Affiliation(s)
- Leice M R de Novais
- Departamento de Química, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | | | - Luiz F Ferreira
- Departamento de Química, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Tereza A N Ribeiro
- Departamento de Química, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Paulo T Sousa
- Departamento de Química, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Marcos J Jacinto
- Departamento de Química, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil
| | - Mário G de Carvalho
- Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
| | - Wagner A S Judice
- Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil.
| | - Larissa O P Jesus
- Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil
| | - Aline A de Souza
- Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil
| | - Heron F V Torquato
- Departamento de Bioquímica, Universidade Federal de São Paulo (Campus São Paulo), São Paulo, Brazil
| | - Edgar J Paredes-Gamero
- Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil
| | - Virginia C Silva
- Departamento de Química, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil.
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Tber Z, Wartenberg M, Jacques JE, Roy V, Lecaille F, Warszycki D, Bojarski AJ, Lalmanach G, Agrofoglio LA. Selective inhibition of human cathepsin S by 2,4,6-trisubstituted 1,3,5-triazine analogs. Bioorg Med Chem 2018; 26:4310-4319. [PMID: 30049585 DOI: 10.1016/j.bmc.2018.07.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 07/10/2018] [Accepted: 07/18/2018] [Indexed: 12/27/2022]
Abstract
We report herein the synthesis and biological evaluation of a new series of 2,4,6-trisubstituted 1,3,5-triazines as reversible inhibitors of human cysteine cathepsins. The desired products bearing morpholine and N-Boc piperidine, respectively, were obtained in three to four steps from commercially available trichlorotriazine. Seventeen hitherto unknown compounds were evaluated in vitro against various cathepsins for their inhibitory properties. Among them, compound 7c (4-(morpholin-4-yl)-6-[4-(trifluoromethoxy)anilino]-1,3,5-triazine-2-carbonitrile) was identified as the most potent and selective inhibitor of cathepsin S (Ki = 2 ± 0.3 nM). Also 7c impaired the autocatalytic maturation of procathepsin S. Molecular docking studies support that 7c bound within the active site of cathepsin S, by interacting with Gly23, Cys25 and Trp26 (S1 subsite), with Asn67, Gly69 and Phe70 (S2 subsite) and with Gln19 (S1' pocket).
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Affiliation(s)
- Zahira Tber
- Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France
| | - Mylène Wartenberg
- INSERM, UMR 1100, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032 Tours cedex, France
| | | | - Vincent Roy
- Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France.
| | - Fabien Lecaille
- INSERM, UMR 1100, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032 Tours cedex, France
| | - Dawid Warszycki
- Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Andrzej J Bojarski
- Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Gilles Lalmanach
- INSERM, UMR 1100, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032 Tours cedex, France
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29
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Roger M, Martínez J, Peiró G, Aparicio JR, Ruiz F, Compañy L, Casellas JA. EUS-FNA cytological material from pancreatic lesions: the expression of cathepsins and its predictive value of malignancy. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 110:446-450. [PMID: 29893579 DOI: 10.17235/reed.2018.4200/2016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS To assess the expression of cathepsins in pancreatic samples obtained by endoscopic ultrasonography and fine needle aspiration (EUS-FNA) and to investigate their relationship with the staging of the pancreatic ductal adenocarcinoma (PDAC). METHODS We prospectively included patients with solid pancreatic masses, in which EUS-FNA were performed. Cathepsins B, L, S and H expression was determined in FNA samples. RESULTS Seventeen FNA were performed. All cytological material was from PDAC. Expression of cathepsins was predominantly low (B 65%, L 23%, S 76%, and H 41%). We found no correlation between the expression levels and the extension of the neoplasm. CONCLUSION Expression of cathepsins in the cytological material of PDAC is diverse but still poor to be useful in the pre-operative diagnosis. There is no correlation between the expression levels of cathepsins and the extension of the PDAC.
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Affiliation(s)
- Manuela Roger
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Juan Martínez
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante
| | - Gloria Peiró
- Servicio de Anatomía Patológica, Hospital General Universitario de Alicante
| | | | - Francisco Ruiz
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Luís Compañy
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
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Endolysosomal Cation Channels and Cancer-A Link with Great Potential. Pharmaceuticals (Basel) 2018; 11:ph11010004. [PMID: 29303993 PMCID: PMC5874700 DOI: 10.3390/ph11010004] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 01/01/2018] [Accepted: 01/04/2018] [Indexed: 12/21/2022] Open
Abstract
The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells.
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Clerc P, Jeanjean P, Hallali N, Gougeon M, Pipy B, Carrey J, Fourmy D, Gigoux V. Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death. J Control Release 2018; 270:120-134. [DOI: 10.1016/j.jconrel.2017.11.050] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/28/2017] [Accepted: 11/30/2017] [Indexed: 12/13/2022]
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John Mary DJS, Manjegowda MC, Kumar A, Dutta S, Limaye AM. The role of cystatin A in breast cancer and its functional link with ERα. J Genet Genomics 2017; 44:593-597. [DOI: 10.1016/j.jgg.2017.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 10/05/2017] [Accepted: 10/23/2017] [Indexed: 10/18/2022]
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Al-Awadhi FH, Law BK, Paul VJ, Luesch H. Grassystatins D-F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer. JOURNAL OF NATURAL PRODUCTS 2017; 80:2969-2986. [PMID: 29087712 PMCID: PMC5764543 DOI: 10.1021/acs.jnatprod.7b00551] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Three new modified peptides named grassystatins D-F (1-3) were discovered from a marine cyanobacterium from Guam. Their structures were elucidated using NMR spectroscopy and mass spectrometry. The hallmark structural feature in the peptides is a statine unit, which contributes to their aspartic protease inhibitory activity preferentially targeting cathepsins D and E. Grassystatin F (3) was the most potent analogue, with IC50 values of 50 and 0.5 nM against cathepsins D and E, respectively. The acidic tumor microenvironment is known to increase the activation of some of the lysosomal proteases associated with tumor metastasis such as cathepsins. Because cathepsin D is a biomarker in aggressive forms of breast cancer and linked to poor prognosis, the effects of cathepsin D inhibition by 1 and 3 on the downstream cellular substrates cystatin C and PAI-1 were investigated. Furthermore, the functional relevance of targeting cathepsin D substrates was evaluated by examining the effect of 1 and 3 on the migration of MDA-MD-231 cells. Grassystatin F (3) inhibited the cleavage of cystatin C and PAI-1, the activities of their downstream targets cysteine cathepsins and tPA, and the migration of the highly aggressive triple negative breast cancer cells, phenocopying the effect of siRNA-mediated knockdown of cathepsin D.
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Affiliation(s)
- Fatma H. Al-Awadhi
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
- Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Brian K. Law
- Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
- Department of Pharmacology and Therapeutics, University of Florida, 1600 Archer Road, Gainesville, Florida 32610, United States
| | - Valerie J. Paul
- Smithsonian Marine Station, 701 Seaway Drive, Fort Pierce, Florida 34949, United States
| | - Hendrik Luesch
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
- Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
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Hispolon suppresses metastasis via autophagic degradation of cathepsin S in cervical cancer cells. Cell Death Dis 2017; 8:e3089. [PMID: 28981104 PMCID: PMC5680581 DOI: 10.1038/cddis.2017.459] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 08/07/2017] [Accepted: 08/09/2017] [Indexed: 12/15/2022]
Abstract
Hispolon, a phenolic compound isolated from Phellinus igniarius, induces apoptosis and anti-tumor effects in cancers. However, the molecular mechanism involved in hispolon-mediated tumor-suppressing activities observed in cervical cancer is poorly characterized. Here, we demonstrated that treatment with hispolon inhibited cell metastasis in two cervical cancer cell lines. In addition, the downregulation of the lysosomal protease Cathepsin S (CTSS) was critical for hispolon-mediated suppression of tumor cell metastasis in both in vitro and in vivo models. Moreover, hispolon induced autophagy, which increased LC3 conversion and acidic vesicular organelle formation. Mechanistically, hispolon inhibited the cell motility of cervical cells through the extracellular signal-regulated kinase (ERK) pathway, and blocking of the ERK pathway reversed autophagy-mediated cell motility and CTSS inhibition. Our results indicate that autophagy is essential for decreasing CTSS activity to inhibit tumor metastasis by hispolon treatment in cervical cancer; this finding provides a new perspective on molecular regulation.
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35
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Raghav N, Singh M. SAR studies of some acetophenone phenylhydrazone based pyrazole derivatives as anticathepsin agents. Bioorg Chem 2017; 75:38-49. [PMID: 28915464 DOI: 10.1016/j.bioorg.2017.08.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 08/18/2017] [Accepted: 08/19/2017] [Indexed: 12/12/2022]
Abstract
Cathepsins have emerged as promising molecular targets in a number of diseases such as Alzeimer's, inflammation and cancer. Elevated cathepsin's levels and decreased cellular inhibitor concentrations have emphasized the search for novel inhibitors of cathepsins. The present work is focused on the design and synthesis of some acetophenone phenylhydrazone based pyrazole derivatives as novel non peptidyl inhibitors of cathepsins B, H and L. The synthesized compounds after characterization have been explored for their inhibitory potency against cathepsins B, H and L. The results show that some of the synthesized compounds exhibit anti-catheptic activity with Ki value of the order of 10-10M. Differential inhibitory effects have been observed for cathepsins B, H and L. Cathepsin L is inhibited more pronounced than cathepsin B and cathepsin H in that order.
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Affiliation(s)
- Neera Raghav
- Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
| | - Mamta Singh
- Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India
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Sun D, Chen Z, Wu M, Zhang Y. Nanomaterial-based Microfluidic Chips for the Capture and Detection of Circulating Tumor Cells. Nanotheranostics 2017; 1:389-402. [PMID: 29071201 PMCID: PMC5647762 DOI: 10.7150/ntno.21268] [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] [Received: 05/31/2017] [Accepted: 07/25/2017] [Indexed: 01/27/2023] Open
Abstract
Circulating tumor cells (CTCs), a type of cancer cells that spreads from primary or metastatic tumors into the bloodstream, can lead to a new fatal metastasis. As a new type of liquid biopsy, CTCs have become a hot pursuit and detection of CTCs offers the possibility for early diagnosis of cancers, earlier evaluation of chemotherapeutic efficacy and cancer recurrence, and choice of individual sensitive anti-cancer drugs. The fundamental challenges of capturing and characterizing CTCs are the extremely low number of CTCs in the blood and the intrinsic heterogeneity of CTCs. A series of microfluidic devices have been proposed for the analysis of CTCs with automation capability, precise flow behaviors, and significant advantages over the conventional larger scale systems. This review aims to provide in-depth insights into CTCs analysis, including various nanomaterial-based microfluidic chips for the capture and detection of CTCs based on the specific biochemical and physical properties of CTCs. The current developmental trends and promising research directions in the establishment of microfluidic chips for the capture and detection of CTCs are also discussed.
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Affiliation(s)
- Duanping Sun
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, P. R. China
| | - Zuanguang Chen
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, P. R. China
| | - Minhao Wu
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, P. R. China
| | - Yuanqing Zhang
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, P. R. China
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Thivyah Prabha A, Sekar D. Deciphering the molecular signaling pathways in breast cancer pathogenesis and their role in diagnostic and treatment modalities. GENE REPORTS 2017; 7:1-17. [DOI: 10.1016/j.genrep.2017.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Berretta M, Alessandrini L, De Divitiis C, Nasti G, Lleshi A, Di Francia R, Facchini G, Cavaliere C, Buonerba C, Canzonieri V. Serum and tissue markers in colorectal cancer: State of art. Crit Rev Oncol Hematol 2017; 111:103-116. [PMID: 28259285 DOI: 10.1016/j.critrevonc.2017.01.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 12/15/2016] [Accepted: 01/10/2017] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers worldwide. It is the second leading cause of cancer death in Western Countries. In the last decade, the survival of patients with metastatic CRC has improved dramatically. Due to the advent of new drugs (irinotecan and oxaliplatin) and target therapies (i.e. bevacizumab, cetuximab, panitumab, aflibercept and regorafenib), the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently. Molecular studies have recently widened the opportunity for testing new possible markers, but actually, only few markers can be recommended for practical use in clinic. In the next future, the hope is to have a complete panel of clinical biomarkers to use in every setting of CRC disease, and at the same time: 1) to receive information about prognostic significance by their expression and 2) to be oriented in the choice of the adequate treatment. Moreover, molecular analyses have shown that the natural history of all CRCs is not the same. Individual patients with same stage tumors may have different long-term prognosis and response to therapy. In addition, some prognostic variables are likely to be more important than others. Here we review the role of serum and tissue markers according to the recently published English literature. This paper is an extension of the article "Biological and clinical markers in colorectal cancer: state of art" by Cappellani A published in Jan 2010.
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Affiliation(s)
- Massimiliano Berretta
- Department of Medical Oncology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy.
| | - Lara Alessandrini
- Division of Pathology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy
| | - Chiara De Divitiis
- Department of Medical Oncology, National Cancer Institute IRCCS Pascale, Naples, Italy
| | - Guglielmo Nasti
- Department of Medical Oncology, National Cancer Institute IRCCS Pascale, Naples, Italy
| | - Arben Lleshi
- Department of Medical Oncology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy
| | - Raffaele Di Francia
- Hematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute IRCCS Pascale, Naples, Italy
| | - Gaetano Facchini
- Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Carla Cavaliere
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy
| | - Carlo Buonerba
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy
| | - Vincenzo Canzonieri
- Division of Pathology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy
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Chen H, Lv M, Lv Z, Li C, Xu W, Zhang W, Zhao X, Duan X, Jin C. Molecular cloning and functional characterization of cathepsin B from the sea cucumber Apostichopus japonicus. FISH & SHELLFISH IMMUNOLOGY 2017; 60:447-457. [PMID: 27847342 DOI: 10.1016/j.fsi.2016.11.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/08/2016] [Accepted: 11/12/2016] [Indexed: 06/06/2023]
Abstract
Cathepsin B (CTSB), a member of lysosomal cysteine protease, is involved in multiple levels of physiological and biological processes, and also plays crucial roles in host immune defense against pathogen infection in vertebrates. However, the function of CTSB within the innate immune system of invertebrates, particularly in marine echinoderms, has been poorly documented. In this study, the immune function of CTSB in Apostichopus japonicus (designated as AjCTSB), a commercially important and disease vulnerable aquaculture specie, was investigated by integrated molecular and protein approaches. A 2153 bp cDNA representing the full-length of AjCTSB was cloned via overlapping ESTs and RACE fragments. AjCTSB contained an open reading frame of 999 bp encoding a secreted protein of 332 amino acid residues with a predicted molecular mass of 36.8 kDa. The deduced amino acid of AjCTSB shared a typical activity center containing three conserved amino acid residues (Cys108, His277 and Asn297). Phylogenetic tree analysis also supported that AjCTSB was a new member of CTSB family with clustering firstly with invertebrate CTSBs. Quantitative real time PCR analysis revealed that AjCTSB was ubiquitously expressed in all examined tissues with the highest levels in intestine. The Vibrio splendidus challenged sea cucumber and LPS-exposed coelomocytes could both significantly boost the expression of AjCTSB. Moreover, the purified recombinant AjCTSB exhibited dose-dependent CTSB activities at the concentration ranged from 0 to 0.24 μg μL-1. Further functional analysis indicated that coelomocytes apoptosis was significantly inhibited by 0.16-fold in vivo and the apoptosis execution Ajcaspase 3 was extremely reduced in Apostichopus japonicus coelomocytes treated with specific AjCTSB siRNA. Collectively, all these results suggested that AjCTSB was an important immune factor and might be served as apoptosis enhancers in pathogen challenged sea cucumber.
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Affiliation(s)
- Huahui Chen
- School of Marine Sciences, Ningbo University, PR China
| | - Miao Lv
- School of Marine Sciences, Ningbo University, PR China
| | - Zhimeng Lv
- School of Marine Sciences, Ningbo University, PR China
| | - Chenghua Li
- School of Marine Sciences, Ningbo University, PR China.
| | - Wei Xu
- Louisiana State University, Agricultural Center, USA
| | - Weiwei Zhang
- School of Marine Sciences, Ningbo University, PR China
| | - Xuelin Zhao
- School of Marine Sciences, Ningbo University, PR China
| | - Xuemei Duan
- School of Marine Sciences, Ningbo University, PR China
| | - Chunhua Jin
- School of Marine Sciences, Ningbo University, PR China
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40
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Mathews PM, Levy E. Cystatin C in aging and in Alzheimer's disease. Ageing Res Rev 2016; 32:38-50. [PMID: 27333827 DOI: 10.1016/j.arr.2016.06.003] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 06/08/2016] [Accepted: 06/08/2016] [Indexed: 12/13/2022]
Abstract
Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer's disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.
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Affiliation(s)
- Paul M Mathews
- Departments of Psychiatry, New York University School of Medicine, USA; Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
| | - Efrat Levy
- Departments of Psychiatry, New York University School of Medicine, USA; Biochemistry and Molecular Pharmacology, New York University School of Medicine, USA; Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
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41
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Martínez JF, Aparicio JR, Peiró G, Cabezas A, Roger M, Ruiz F, Compañy L, Casellas JA. Study of the expression of cathepsins in histological material from pancreatic lesions. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2016; 108:780-784. [PMID: 27855482 DOI: 10.17235/reed.2016.3749/2015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS To assess the expression levels of cathepsins in malignant and premalignant lesions. METHODS We retrospectively included patients who underwent pancreatic surgery on pancreatic solid or cystic masses. The expression of cathepsin H, L, B and S was determined in both types of samples. Lesions were divided into three categories: malignant (pancreatic adenocarcinoma and malignant mucinous neoplasms), premalignant (mucinous neoplasms) and benign (other lesions). RESULTS Thirty-one surgical resection samples were studied. The expression of cathepsins was significantly higher in malignant lesions than in premalignant and benign lesions (H 75%, 27%, 37% p = 0.05; L 92%, 36%, 37% p = 0.011; B 83%, 36%, 62% p = 0.069; S 92%, 36%, 25% p = 0.004, respectively). CONCLUSIONS Cathepsins are overexpressed in histological samples of malignant lesions compared to premalignant and benign lesions. However, the expression of cathepsins is similar in both premalignant and benign lesions.
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Affiliation(s)
- Juan F Martínez
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - José Ramón Aparicio
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Gloria Peiró
- Servicio de Anatomía Patológica, Hospital General Universitario de Alicante, España
| | - Antonio Cabezas
- Servicio de Anatomía Patológica, Hospital General Universitario de Alicante, España
| | - Manuela Roger
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Francisco Ruiz
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Luís Compañy
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
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An anti-EpCAM antibody EpAb2-6 for the treatment of colon cancer. Oncotarget 2016; 6:24947-68. [PMID: 26317650 PMCID: PMC4694806 DOI: 10.18632/oncotarget.4453] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 07/24/2015] [Indexed: 02/07/2023] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is known to be overexpressed in epithelial cancers associated with enhanced malignant potential, particularly colorectal carcinoma (CRC) and head and neck squamous cell carcinoma (HNSCC). However, it is unknown whether progression of malignance can be directly inhibited by targeting EpCAM. Here, we have generated five novel monoclonal antibodies (mAbs) against EpCAM. One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts. EpAb2-6 also increases the therapeutic efficacy of irinotecan, fluorouracil, and leucovorin (IFL) therapy in a colon cancer animal model and gemcitabine therapy in a pancreatic cancer animal model. Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation. Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.
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43
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Wan QS, Zhang KH. Noninvasive detection of gastric cancer. Tumour Biol 2016; 37:11633-11643. [PMID: 27381515 DOI: 10.1007/s13277-016-5129-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 06/29/2016] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third common cause of cancer death worldwide. Endoscopy is the most effective method for GC screening, but its application is limited by the invasion. Therefore, continuous efforts have been made to develop noninvasive methods for GC detection and promising results have been reported. Here, we review the advances in GC detection by protein and nucleic acid tumor markers, circulating tumor cells, and tumor-associated autoantibodies in peripheral blood. Some potential new noninvasive methods for GC detection are also reviewed, including exhaled breath analysis, blood spectroscopy analysis and molecular imaging.
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Affiliation(s)
- Qin-Si Wan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, 17 Yongwai Zheng Street, Nanchang, Jiangxi, 330006, China
| | - Kun-He Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, 17 Yongwai Zheng Street, Nanchang, Jiangxi, 330006, China.
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Abstract
Cathepsins are proteases found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, their catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Cathepsins have been identified as therapeutic targets in the search for new drugs against a number of human pathologies, including cancer, Alzheimer's, and osteoporosis. A number of natural products have been reported as selective inhibitors of some cathepsins. Chemical structure of natural products as inhibitors of cathepsins can be very diverse. Some peptidic natural products are inhibitors of the cysteine protease cathepsins such as E-64 isolated from Aspergillus, which is a cathepsin B inhibitor, or more recently the marine cyanobacterial metabolite gallinamide A which is a selective inhibitor of human cathepsin L. Also amino acid derivatives have been reported as inhibitors of cathepsin A. Other natural products include chalcone natural products possessing cytotoxic activities against prostate cancer cells and inhibiting cysteine cathepsins in vitro, antipain and its analogues isolated from Streptomyces as inhibitors of cathepsin K, and natural biflavones as novel inhibitors of cathepsins B and K. In this review we will report the most representative examples of natural products as inhibitors of cathepsins, especially the ones reported during the last decade.
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45
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Lysosomal cysteine peptidases – Molecules signaling tumor cell death and survival. Semin Cancer Biol 2015; 35:168-79. [DOI: 10.1016/j.semcancer.2015.08.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 07/31/2015] [Accepted: 08/03/2015] [Indexed: 12/18/2022]
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46
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Sun BG, Hu YH. Identification, mRNA expression profiling and activity characterization of cathepsin L from red drum (Sciaenops ocellatus). FISH PHYSIOLOGY AND BIOCHEMISTRY 2015; 41:1463-1473. [PMID: 26164862 DOI: 10.1007/s10695-015-0099-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 07/07/2015] [Indexed: 06/04/2023]
Abstract
Cathepsin L is a cysteine protease with a papain-like structure. It is known to be implicated in multiple processes of mammalian immune response to pathogen infection. In teleost fish, the functionality of cathepsin L is less understood. In this work, we characterized a cathepsin L homologue (designated as SoCatL) from red drum Sciaenops ocellatus, an important farmed fish species in China. SoCatL possesses a typical domain arrangement characteristic of cathepsin L, which comprises a proregion and a protease domain with four catalytically essential residues (Gln137, Cys143, His282 and Asn302) conserved in various organisms. SoCatL shares moderate sequence identities with mammalian cathepsin L and relatively high sequence identities with teleost cathepsin L. Phylogenetic analysis revealed that SoCatL is evolutionally close to fish cathepsin L, especially those belonging to the Perciformes order. The homology model of SoCatL was discovered to exhibit a structure resembling human cathepsin L. Transcriptional expression of SoCatL was found ubiquitous in tissues and enhanced after experimental infection with a bacterial pathogen. Recombinant SoCatL purified from Escherichia coli (designated as rSoCatL) displayed apparent proteolytic activity, which was optimal at 50 °C and pH 7.0. The activity of rSoCatL required the catalytic residue Cys143 and was severely reduced by cathepsin inhibitor. These results suggest that SoCatL is a teleost cathepsin L homologue which functions as a cysteine protease and is likely to participate in the host immune response against bacterial infection.
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Affiliation(s)
- Bo-guang Sun
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao, 266071, China
| | - Yong-hua Hu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao, 266071, China.
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Johnson IR, Parkinson-Lawrence EJ, Keegan H, Spillane CD, Barry-O'Crowley J, Watson WR, Selemidis S, Butler LM, O'Leary JJ, Brooks DA. Endosomal gene expression: a new indicator for prostate cancer patient prognosis? Oncotarget 2015; 6:37919-29. [PMID: 26473288 PMCID: PMC4741974 DOI: 10.18632/oncotarget.6114] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 09/28/2015] [Indexed: 12/31/2022] Open
Abstract
Prostate cancer continues to be a major cause of morbidity and mortality in men, but a method for accurate prognosis in these patients is yet to be developed. The recent discovery of altered endosomal biogenesis in prostate cancer has identified a fundamental change in the cell biology of this cancer, which holds great promise for the identification of novel biomarkers that can predict disease outcomes. Here we have identified significantly altered expression of endosomal genes in prostate cancer compared to non-malignant tissue in mRNA microarrays and confirmed these findings by qRT-PCR on fresh-frozen tissue. Importantly, we identified endosomal gene expression patterns that were predictive of patient outcomes. Two endosomal tri-gene signatures were identified from a previously published microarray cohort and had a significant capacity to stratify patient outcomes. The expression of APPL1, RAB5A, EEA1, PDCD6IP, NOX4 and SORT1 were altered in malignant patient tissue, when compared to indolent and normal prostate tissue. These findings support the initiation of a case-control study using larger cohorts of prostate tissue, with documented patient outcomes, to determine if different combinations of these new biomarkers can accurately predict disease status and clinical progression in prostate cancer patients.
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Affiliation(s)
- Ian R.D. Johnson
- Mechanisms in Cell Biology and Disease Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia
| | - Emma J. Parkinson-Lawrence
- Mechanisms in Cell Biology and Disease Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia
| | - Helen Keegan
- Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
| | - Cathy D. Spillane
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
| | | | - William R. Watson
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Stavros Selemidis
- Infection and Immunity Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Lisa M. Butler
- Prostate Cancer Research Group, School of Medicine and Freemasons Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia
| | - John J. O'Leary
- Department of Pathology, Coombe Women and Infants University Hospital, Dublin, Ireland
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
| | - Doug A. Brooks
- Mechanisms in Cell Biology and Disease Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia
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Li YQ, Chandran BK, Lim CT, Chen X. Rational Design of Materials Interface for Efficient Capture of Circulating Tumor Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2015; 2:1500118. [PMID: 27980914 PMCID: PMC5115340 DOI: 10.1002/advs.201500118] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 05/25/2015] [Indexed: 05/11/2023]
Abstract
Originating from primary tumors and penetrating into blood circulation, circulating tumor cells (CTCs) play a vital role in understanding the biology of metastasis and have great potential for early cancer diagnosis, prognosis and personalized therapy. By exploiting the specific biophysical and biochemical properties of CTCs, various material interfaces have been developed for the capture and detection of CTCs from blood. However, due to the extremely low number of CTCs in peripheral blood, there exists a need to improve the efficiency and specificity of the CTC capture and detection. In this regard, a critical review of the numerous reports of advanced platforms for highly efficient and selective capture of CTCs, which have been spurred by recent advances in nanotechnology and microfabrication, is essential. This review gives an overview of unique biophysical and biochemical properties of CTCs, followed by a summary of the key material interfaces recently developed for improved CTC capture and detection, with focus on the use of microfluidics, nanostructured substrates, and miniaturized nuclear magnetic resonance-based systems. Challenges and future perspectives in the design of material interfaces for capture and detection of CTCs in clinical applications are also discussed.
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Affiliation(s)
- Yong-Qiang Li
- School of Materials Science and Engineering Nanyang Technological University 50 Nanyang Avenue SIngapore 639798 Singapore; School of Radiation Medicine and Protection and School for Radiological and Interdisciplinary Sciences (RAD-X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions Medical College of Soochow University Suzhou Jiangsu 215123 China
| | - Bevita K Chandran
- School of Materials Science and Engineering Nanyang Technological University 50 Nanyang Avenue SIngapore 639798 Singapore
| | - Chwee Teck Lim
- Department of Biomedical Engineering Mechanobiology Institute Centre for Advanced 2D Materials National University of Singapore 9 Engineering Drive 1 Singapore 117575 Singapore
| | - Xiaodong Chen
- School of Materials Science and Engineering Nanyang Technological University 50 Nanyang Avenue SIngapore 639798 Singapore
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Burton LJ, Smith BA, Smith BN, Loyd Q, Nagappan P, McKeithen D, Wilder CL, Platt MO, Hudson T, Odero-Marah VA. Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells. Carcinogenesis 2015; 36:1019-27. [PMID: 26069256 PMCID: PMC4643647 DOI: 10.1093/carcin/bgv084] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 05/21/2015] [Accepted: 06/03/2015] [Indexed: 11/12/2022] Open
Abstract
To develop new and effective chemopreventive agents against bone metastasis, we assessed the effects of muscadine grape skin extract (MSKE), whose main bioactive component is anthocyanin, on bone turnover, using prostate and breast cancer cell models overexpressing Snail transcription factor. MSKE has been shown previously to promote apoptosis in prostate cancer cells without affecting normal prostate epithelial cells. Snail is overexpressed in prostate and breast cancer, and is associated with increased invasion, migration and bone turnover/osteoclastogenesis. Cathepsin L (CatL) is a cysteine cathepsin protease that is overexpressed in cancer and involved in bone turnover. Snail overexpression in prostate (LNCaP, ARCaP-E) and breast (MCF-7) cancer cells led to increased CatL expression/activity and phosphorylated STAT-3 (pSTAT-3), compared to Neo vector controls, while the reverse was observed in C4-2 (the aggressive subline of LNCaP) cells with Snail knockdown. Moreover, CatL expression was higher in prostate and breast tumor tissue compared to normal tissue. MSKE decreased Snail and pSTAT3 expression, and abrogated Snail-mediated CatL activity, migration and invasion. Additionally, Snail overexpression promoted osteoclastogenesis, which was significantly inhibited by the MSKE as effectively as Z-FY-CHO, a CatL-specific inhibitor, or osteoprotegerin, a receptor activator of nuclear factor kappa B ligand (RANKL) antagonist. Overall, these novel findings suggest that Snail regulation of CatL may occur via STAT-3 signaling and can be antagonized by MSKE, leading to decreased cell invasion, migration and bone turnover. Therefore, inhibition using a natural product such as MSKE could potentially be a promising bioactive compound for bone metastatic cancer.
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Affiliation(s)
- Liza J Burton
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Basil A Smith
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Bethany N Smith
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Quentin Loyd
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Peri Nagappan
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Danielle McKeithen
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Catera L Wilder
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and
| | - Manu O Platt
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and
| | - Tamaro Hudson
- Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Valerie A Odero-Marah
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA
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Borišek J, Vizovišek M, Sosnowski P, Turk B, Turk D, Mohar B, Novič M. Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors. J Med Chem 2015; 58:6928-37. [PMID: 26280490 DOI: 10.1021/acs.jmedchem.5b00746] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.
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Affiliation(s)
- Jure Borišek
- National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
| | - Matej Vizovišek
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia
| | - Piotr Sosnowski
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia
| | - Boris Turk
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.,Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia
| | - Dušan Turk
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.,Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.,Faculty of Chemistry and Chemical Technology, University of Ljubljana , Večna pot 113, SI-1000 Ljubljana, Slovenia
| | - Barbara Mohar
- National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
| | - Marjana Novič
- National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
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