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Lee CS, Shang R, Wang F, Khayambashi P, Wang H, Araujo G, Puri K, Vlodavsky I, Hussein B, Rodrigues B. Heparanase Stimulation of Physiologic Cardiac Hypertrophy Is Suppressed After Chronic Diabetes, Resulting in Cardiac Remodeling and Dysfunction. Diabetes 2024; 73:1300-1316. [PMID: 38771953 DOI: 10.2337/db24-0217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 05/09/2024] [Indexed: 05/23/2024]
Abstract
In addition to controlling smooth muscle tone in coronary vessels, endothelial cells also influence subjacent cardiomyocyte growth. Because heparanase, with exclusive expression in endothelial cells, enables extracellular matrix remodeling, angiogenesis, metabolic reprogramming, and cell survival, it is conceivable that it could also encourage development of cardiac hypertrophy. Global heparanase overexpression resulted in physiologic cardiac hypertrophy, likely an outcome of HSPG clustering and activation of hypertrophic signaling. The heparanase autocrine effect of releasing neuregulin-1 could have also contributed to this overexpression. Hyperglycemia induced by streptozotocin-induced diabetes sensitized the heart to flow-induced release of heparanase and neuregulin-1. Despite this excess secretion, progression of diabetes caused significant gene expression changes related to mitochondrial metabolism and cell death that led to development of pathologic hypertrophy and heart dysfunction. Physiologic cardiac hypertrophy was also observed in rats with cardiomyocyte-specific vascular endothelial growth factor B overexpression. When perfused, hearts from these animals released significantly higher amounts of both heparanase and neuregulin-1. However, subjecting these animals to diabetes triggered robust transcriptome changes related to metabolism and a transition to pathologic hypertrophy. Our data suggest that in the absence of mechanisms that support cardiac energy generation and prevention of cell death, as seen after diabetes, there is a transition from physiologic to pathologic cardiac hypertrophy and a decline in cardiac function. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Chae Syng Lee
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Rui Shang
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Fulong Wang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Parisa Khayambashi
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hualin Wang
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gala Araujo
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Karanjit Puri
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Israel Vlodavsky
- Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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2
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Feng F, Wang LJ, Li JC, Chen TT, Liu L. Role of heparanase in ARDS through autophagy and exosome pathway (review). Front Pharmacol 2023; 14:1200782. [PMID: 37361227 PMCID: PMC10285077 DOI: 10.3389/fphar.2023.1200782] [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] [Received: 04/05/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is the most common respiratory disease in ICU. Although there are many treatment and support methods, the mortality rate is still high. The main pathological feature of ARDS is the damage of pulmonary microvascular endothelium and alveolar epithelium caused by inflammatory reaction, which may lead to coagulation system disorder and pulmonary fibrosis. Heparanase (HPA) plays an significant role in inflammation, coagulation, fibrosis. It is reported that HPA degrades a large amount of HS in ARDS, leading to the damage of endothelial glycocalyx and inflammatory factors are released in large quantities. HPA can aggrandize the release of exosomes through syndecan-syntenin-Alix pathway, leading to a series of pathological reactions; at the same time, HPA can cause abnormal expression of autophagy. Therefore, we speculate that HPA promotes the occurrence and development of ARDS through exosomes and autophagy, which leads to a large amount of release of inflammatory factors, coagulation disorder and pulmonary fibrosis. This article mainly describes the mechanism of HPA on ARDS.
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Affiliation(s)
- Fei Feng
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Lin-Jun Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Jian-Chun Li
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Ting-Ting Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Liping Liu
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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3
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Zhang Y, Li Y, Huang S, Zhang H, Lin Q, Gong T, Sun X, Zhang Z, Zhang L. Enhanced anti-metastatic therapy with down-regulation of heparinase expression by ROS-responsive micellar nanoparticles. NANOSCALE 2021; 13:15267-15277. [PMID: 34477185 DOI: 10.1039/d1nr02964a] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Metastasis is a major sign of malignant tumors which plays a vital role in cancer-related death. Suppressing metastasis is an important way to improve the survival rate of cancer patients. Herein, multifunctional PEG-LAM-PPS nanoparticles (nPLPs) are fabricated as both nanocarriers and anti-metastatic agents for tumor treatment. In this system, laminarin sulfate (LAM) suppresses metastasis by reducing heparinase and protecting the extracellular matrix; the ROS-sensitive polypropylene sulfide (PPS) improves the release of the loaded drug in the tumor microenvironment. This is the first time that laminarin sulfate has been used as a carrier to inhibit the expression of heparinase and treat melanoma lung metastasis. The blank nanoparticles are excellently safe and showed high anti-metastatic efficacy in melanoma lung metastatic mouse models, reducing metastatic nodules by 60%. They significantly improved the anti-tumor efficacy of the loaded drug doxorubicin, provided ∼33% further reduction of the tumor volume and 50% further reduction of the metastatic nodule number compared with free doxorubicin. Thus, these simple and versatile micellar nanoparticles composed of biocompatible materials offer a promising vehicle for treating invasive solid tumors and metastases.
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Affiliation(s)
- Yicong Zhang
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Yuai Li
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Shiqi Huang
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Hanming Zhang
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Qing Lin
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Tao Gong
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Xun Sun
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Zhirong Zhang
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
| | - Ling Zhang
- West China School of Pharmacy, College of Polymer Science and Engineering, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu, 610041, P. R. China.
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Kaur R, Deb PK, Diwan V, Saini B. Heparanase Inhibitors in Cancer Progression: Recent Advances. Curr Pharm Des 2021; 27:43-68. [PMID: 33185156 DOI: 10.2174/1381612826666201113105250] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 08/25/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND An endo-β-glucuronidase enzyme, Heparanase (HPSE), degrades the side chains of polymeric heparan sulfate (HS), a glycosaminoglycan formed by alternate repetitive units of D-glucosamine and D-glucuronic acid/L-iduronic acid. HS is a major component of the extracellular matrix and basement membranes and has been implicated in processes of the tissue's integrity and functional state. The degradation of HS by HPSE enzyme leads to conditions like inflammation, angiogenesis, and metastasis. An elevated HPSE expression with a poor prognosis and its multiple roles in tumor growth and metastasis has attracted significant interest for its inhibition as a potential anti-neoplastic target. METHODS We reviewed the literature from journal publication websites and electronic databases such as Bentham, Science Direct, PubMed, Scopus, USFDA, etc., about HPSE, its structure, functions, and role in cancer. RESULTS The present review is focused on Heparanase inhibitors (HPIns) that have been isolated from natural resources or chemically synthesized as new therapeutics for metastatic tumors and chronic inflammatory diseases in recent years. The recent developments made in the HPSE structure and function are also discussed, which can lead to the future design of HPIns with more potency and specificity for the target. CONCLUSION HPIns can be a better target to be explored against various cancers.
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Affiliation(s)
- Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Pran Kishore Deb
- Faculty of Pharmacy, Philadelphia University, Philadelphia, Jordan
| | - Vishal Diwan
- Faculty of Medicine, The University of Queensland, Queensland, Australia
| | - Balraj Saini
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Zhou L, Yin R, Gao N, Sun H, Chen D, Cai Y, Ren L, Yang L, Zuo Z, Zhang H, Zhao J. Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis. Pharmacol Res 2021; 166:105527. [PMID: 33667689 DOI: 10.1016/j.phrs.2021.105527] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/10/2021] [Accepted: 02/28/2021] [Indexed: 01/05/2023]
Abstract
The invasion and metastasis of tumor cells are the hallmarks of malignant diseases and the greatest obstacle to overcome. Heparanase-mediated degradation of heparan sulfate (HS) is the critical process for tumor angiogenesis and metastasis, therefore, heparanase become an attractive target for cancer research. Herein, we reported a native fucosylated glycosaminoglycan (nHG) extracted from sea cucumber Holothuria fuscopunctata and a depolymerized nHG (dHG) and its contained oligosaccharides (hs17, hs14, hs11, hs8 and hs5), acting as heparanase inhibitors. nHG and its derivatives have the ability to bind with heparanase directly, leading to significant inhibition of heparanase activity. Moreover, their apparent binding affinity to heparanase was comparable to their inhibitory effect, which was elevated along with the increase of chain length, similar to the effect of heparins. In addition, oligosaccharides inhibited the migration and invasion of 4T1 mammary carcinoma cells and human umbilical vein endothelial cells (HUVECs) and also suppressed tube formation in Matrigel matrix and angiogenesis in the chick chorioallantoic membrane (CAM) assay. In the metastatic mouse model, oligosaccharides exhibited practical antimetastatic effects on 4T1 mammary carcinoma cells. According to the reported anticoagulant activity and the low bleeding tendency of dHG and its oligosaccharides, the use of the oligosaccharides may lead to better effects on tumor patients with thrombosis tendency.
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Affiliation(s)
- Lutan Zhou
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Ronghua Yin
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China
| | - Na Gao
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China
| | - Huifang Sun
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Dingyuan Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ying Cai
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lin Ren
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Lian Yang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Zhili Zuo
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
| | - Hongbin Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China.
| | - Jinhua Zhao
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China.
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6
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Ahrens TD, Bang-Christensen SR, Jørgensen AM, Løppke C, Spliid CB, Sand NT, Clausen TM, Salanti A, Agerbæk MØ. The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis. Front Cell Dev Biol 2020; 8:749. [PMID: 32984308 PMCID: PMC7479181 DOI: 10.3389/fcell.2020.00749] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/17/2020] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.
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Affiliation(s)
- Theresa D. Ahrens
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sara R. Bang-Christensen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
| | | | - Caroline Løppke
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Charlotte B. Spliid
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Nicolai T. Sand
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas M. Clausen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ali Salanti
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mette Ø. Agerbæk
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
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7
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Elgundi Z, Papanicolaou M, Major G, Cox TR, Melrose J, Whitelock JM, Farrugia BL. Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan. Front Oncol 2020; 9:1482. [PMID: 32010611 PMCID: PMC6978720 DOI: 10.3389/fonc.2019.01482] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 12/10/2019] [Indexed: 12/12/2022] Open
Abstract
Cancer metastasis is the dissemination of tumor cells to new sites, resulting in the formation of secondary tumors. This process is complex and is spatially and temporally regulated by intrinsic and extrinsic factors. One important extrinsic factor is the extracellular matrix, the non-cellular component of tissues. Heparan sulfate proteoglycans (HSPGs) are constituents of the extracellular matrix, and through their heparan sulfate chains and protein core, modulate multiple events that occur during the metastatic cascade. This review will provide an overview of the role of the extracellular matrix in the events that occur during cancer metastasis, primarily focusing on perlecan. Perlecan, a basement membrane HSPG is a key component of the vascular extracellular matrix and is commonly associated with events that occur during the metastatic cascade. Its contradictory role in these events will be discussed and we will highlight the recent advances in cancer therapies that target HSPGs and their modifying enzymes.
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Affiliation(s)
- Zehra Elgundi
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
| | - Michael Papanicolaou
- The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, UNSW Sydney, Darlinghurst, NSW, Australia.,School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia
| | - Gretel Major
- The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Thomas R Cox
- The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, UNSW Sydney, Darlinghurst, NSW, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - James Melrose
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.,Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, Australia
| | - John M Whitelock
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
| | - Brooke L Farrugia
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.,Department of Biomedical Engineering, Melbourne School of Engineering, The University of Melbourne, Melbourne, VIC, Australia
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8
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Shang R, Lal N, Puri K, Hussein B, Rodrigues B. Involvement of Heparanase in Endothelial Cell-Cardiomyocyte Crosstalk. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:721-745. [PMID: 32274734 DOI: 10.1007/978-3-030-34521-1_30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Traditionally, the management of diabetes has focused mainly on controlling high blood glucose levels. Unfortunately, despite valiant efforts to normalize this blood glucose, poor medication management predisposes these patients to heart failure. Following diabetes, how the heart utilizes different sources of fuel for energy is key to the development of heart failure. The diabetic heart switches from using both glucose and fats, to predominately using fats as an energy resource for maintaining its activities. This transformation to using fats as an exclusive source of energy is helpful in the initial stages of the disease and is tightly controlled. However, over the progression of diabetes, there is a loss of this controlled supply and use of fats, which ultimately has terrible consequences since the uncontrolled use of fats produces toxic by-products which weaken heart function and cause heart disease. Heparanase is a key player that directs how much fats are provided to the heart and does so in association with several partners like LPL and VEGFs. Together, they regulate the amount of fats supplied, and their subsequent breakdown to provide energy. Following diabetes, there is a disruption in this network resulting in fat oversupply and cell death. Understanding how the heparanase-LPL-VEGFs "ensemble" cooperates, and its dysfunction in the diabetic heart would be useful in restoring metabolic equilibrium and limiting diabetes-related cardiac damage.
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Affiliation(s)
- Rui Shang
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Nathaniel Lal
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Karanjit Puri
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
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9
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Tang B, Yang S. Involvement of Heparanase in Gastric Cancer Progression and Immunotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:351-363. [PMID: 32274717 DOI: 10.1007/978-3-030-34521-1_13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Heparanase is upregulated in various tumors, and its expression is closely associated with tumor growth, angiogenesis and metastasis, which accomplishes this mainly through degrading heparan sulfate and releasing heparin-binding growth factors thereby influencing multiple signaling pathways. In addition to its enzymatic degrading activity, heparanase can act via its non-enzymatic mechanisms that directly regulate various signaling. This review mainly focuses on the expression levels and role of heparanase in gastric cancer, and multiple genes and mechanisms regulating heparanase expression in gastric cancer. Furthermore, the development of heparanase-targeted immunotherapy and its potential application for treating gastric cancer are discussed.
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Affiliation(s)
- Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
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10
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Vlodavsky I, Sanderson RD, Ilan N. Forty Years of Basic and Translational Heparanase Research. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:3-59. [PMID: 32274705 PMCID: PMC7142273 DOI: 10.1007/978-3-030-34521-1_1] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This review summarizes key developments in the heparanase field obtained 20 years prior to cloning of the HPSE gene and nearly 20 years after its cloning. Of the numerous publications and review articles focusing on heparanase, we have selected those that best reflect the progression in the field as well as those we regard important accomplishments with preference to studies performed by scientists and groups that contributed to this book. Apart from a general 'introduction' and 'concluding remarks', the abstracts of these studies are presented essentially as published along the years. We apologize for not being objective and not being able to include some of the most relevant abstracts and references, due to space limitation. Heparanase research can be divided into two eras. The first, initiated around 1975, dealt with identifying the enzyme, establishing the relevant assay systems and investigating its biological activities and significance in cancer and other pathologies. Studies performed during the first area are briefly introduced in a layman style followed by the relevant abstracts presented chronologically, essentially as appears in PubMed. The second era started in 1999 when the heparanase gene was independently cloned by 4 research groups [1-4]. As expected, cloning of the heparanase gene boosted heparanase research by virtue of the readily available recombinant enzyme, molecular probes, and anti-heparanase antibodies. Studies performed during the second area are briefly introduced followed by selected abstracts of key findings, arranged according to specific topics.
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Affiliation(s)
- Israel Vlodavsky
- Technion Integrated Cancer Center (TICC) Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Haifa Israel
| | - Ralph D. Sanderson
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL USA
| | - Neta Ilan
- Technion Integrated Cancer Center (TICC) Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Haifa Israel
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11
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Chen SC, Yen MC, Chen FW, Wu LY, Yang SJ, Kuo PL, Hsu YL. Knockdown of GA-binding protein subunit β1 inhibits cell proliferation via p21 induction in renal cell carcinoma. Int J Oncol 2018; 53:886-894. [PMID: 29845229 DOI: 10.3892/ijo.2018.4411] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 05/04/2018] [Indexed: 11/05/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. In the present study, bioinformatics tools were systematically used to investigate the potential upstream effector involved in the progression of ccRCC. Using the Gene Expression Omnibus database and Library of Integrated Network-based Cellular Signatures L1000 platform, it was identified that GA-binding protein subunit β1 (GABPB1) was a potential effector gene. GABPB1 is a transcription factor subunit and its function in ccRCC is unclear. Elevated expression of GABPB1 mRNA in ccRCC was also observed in other clinical datasets from the Oncomine database. Following reverse transcription-quantitative polymerase chain reaction and western blot analysis, the ccRCC 786-O and A498 cell lines showed higher expression levels of GABPB1 than HK-2, a normal kidney cell line. Knockdown of GABPB1 in the 786-O and A498 cells significantly decreased the ability to form colonies by inducing the expression of p21Waf/Cip1. SurvExpress database analysis indicated that a higher expression of GABPB1 was associated with poor survival outcome in patients with renal cancer. These findings imply that GABPB1 serves an important role in the progression of ccRCC.
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Affiliation(s)
- Szu-Chia Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Feng-Wei Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Ling-Yu Wu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Shiang-Jie Yang
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Po-Lin Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Ya-Ling Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
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12
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Jin H, Cui M. Gene silencing of heparanase results in suppression of invasion and migration of gallbladder carcinoma cells. Biosci Biotechnol Biochem 2018; 82:1116-1122. [PMID: 29598788 DOI: 10.1080/09168451.2018.1456316] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
This study investigated the effect of transcriptional gene silencing of the heparanase gene on standard gallbladder carcinoma cells (GBC-SD). The miRNAs targeting the promoter region and coding region of the heparanase gene were designed and synthesized. We transfected four recombinant miRNA vectors into GBC-SD. We performed the wound healing assays and invasion assays. The result shows that the heparanase expression was significantly decreased by recombinant vectors in transfected GBC-SD cells (p < 0.01), of which pmiR-Hpa-2 showed best interference effect (p < 0.05). The penetrated and migrating cells numbers and adherence rate of GBC-SD cells were significantly decreased by pmiR-Hpa-2 (p < 0.05).
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Affiliation(s)
- Hao Jin
- a The Second Department of General Surgery , Zhuhai People's Hospital , Zhuhai , China
| | - Min Cui
- a The Second Department of General Surgery , Zhuhai People's Hospital , Zhuhai , China
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13
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Chiu APL, Wan A, Rodrigues B. Cardiomyocyte-endothelial cell control of lipoprotein lipase. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1434-41. [PMID: 26995461 DOI: 10.1016/j.bbalip.2016.03.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/14/2016] [Accepted: 03/15/2016] [Indexed: 01/17/2023]
Abstract
In people with diabetes, inadequate pharmaceutical management predisposes the patient to heart failure, which is the leading cause of diabetes related death. One instigator for this cardiac dysfunction is change in fuel utilization by the heart. Thus, following diabetes, when cardiac glucose utilization is impaired, the heart undergoes metabolic transformation wherein it switches to using fats as an exclusive source of energy. Although this switching is geared to help the heart initially, in the long term, this has detrimental effects on cardiac function. These include the generation of noxious byproducts, which damage the cardiomyocytes, and ultimately result in increased morbidity and mortality. A key perpetrator that may be responsible for organizing this metabolic disequilibrium is lipoprotein lipase (LPL), the enzyme responsible for providing fat to the hearts. Either exaggeration or reduction in its activity following diabetes could lead to heart dysfunction. Given the disturbing news that diabetes is rampant across the globe, gaining more insight into the mechanism(s) by which cardiac LPL is regulated may assist other researchers in devising new therapeutic strategies to restore metabolic equilibrium, to help prevent or delay heart disease seen during diabetes. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
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Affiliation(s)
- Amy Pei-Ling Chiu
- Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
| | - Andrea Wan
- Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
| | - Brian Rodrigues
- Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
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14
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Mikami S, Oya M, Mizuno R, Kosaka T, Katsube KI, Okada Y. Invasion and metastasis of renal cell carcinoma. Med Mol Morphol 2013; 47:63-7. [PMID: 24213520 DOI: 10.1007/s00795-013-0064-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 10/21/2013] [Indexed: 02/02/2023]
Abstract
Renal cell carcinoma (RCC) represents over 80% of kidney cancer, and about 30% of the patients with RCC develop metastasis after the surgery. Invasion of basement membrane (BM) and extracellular matrix (ECM) is an essential event in tumor invasion and metastasis. Matrix metalloproteinases (MMPs), which digest the main components of BM and ECM, are expressed in RCC. Heparanase, which degrades heparan sulfate proteoglycans, is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis. Bone metastasis is common among the patients with RCC, and increased osteoclastic activity was observed at metastatic sites. Receptor activator of nuclear factor κB ligand (RANKL), which plays an important role in osteoclastogenesis, is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis. Epithelial-mesenchymal transition (EMT), a switch of epithelial cells to sarcomatoid phenotype, is considered to be critical step during metastasis, and Snail, a major regulator of EMT, is predominantly expressed in high-grade RCC, and high Snail expression is a worse prognostic factor. Accordingly, heparanase, RANKL and Snail may be targets for the development of anti-tumor therapies for RCCs.
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Affiliation(s)
- Shuji Mikami
- Division of Diagnostic Pathology, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan,
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15
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Zhang D, Wan A, Chiu APL, Wang Y, Wang F, Neumaier K, Lal N, Bround MJ, Johnson JD, Vlodavsky I, Rodrigues B. Hyperglycemia-induced secretion of endothelial heparanase stimulates a vascular endothelial growth factor autocrine network in cardiomyocytes that promotes recruitment of lipoprotein lipase. Arterioscler Thromb Vasc Biol 2013; 33:2830-8. [PMID: 24115032 DOI: 10.1161/atvbaha.113.302222] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE During diabetes mellitus, coronary lipoprotein lipase increases to promote the predominant use of fatty acids. We have reported that high glucose stimulates active heparanase secretion from endothelial cells to cleave cardiomyocyte heparan sulfate and release bound lipoprotein lipase for transfer to the vascular lumen. In the current study, we examined whether heparanase also has a function to release cardiomyocyte vascular endothelial growth factor (VEGF), and whether this growth factor influences cardiomyocyte fatty acid delivery in an autocrine manner. APPROACH AND RESULTS Acute, reversible hyperglycemia was induced in rats, and a modified Langendorff heart perfusion was used to separate the coronary perfusate from the interstitial effluent. Coronary artery endothelial cells were exposed to high glucose to generate conditioned medium, and VEGF release from isolated cardiomyocytes was tested using endothelial cell conditioned medium or purified active and latent heparanase. Autocrine signaling of myocyte-derived VEGF on cardiac metabolism was studied. High glucose promoted latent and active heparanase secretion into endothelial cell conditioned medium, an effective stimulus for releasing cardiomyocyte VEGF. Intriguingly, latent heparanase was more efficient than active heparanase in releasing VEGF from a unique cell surface pool. VEGF augmented cardiomyocyte intracellular calcium and AMP-activated protein kinase phosphorylation and increased heparin-releasable lipoprotein lipase. CONCLUSIONS Our data suggest that the heparanase-lipoprotein lipase-VEGF axis amplifies fatty acid delivery, a rapid and adaptive mechanism that is geared to overcome the loss of glucose consumption by the diabetic heart. If prolonged, the resultant lipotoxicity could lead to cardiovascular disease in humans.
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Affiliation(s)
- Dahai Zhang
- From the Faculty of Pharmaceutical Sciences (D.Z., A.W., A.P.-L.C., Y.W., F.W., K.N., N.L., B.R.), and Department of Cellular and Physiological Sciences (M.J.B., J.D.J.), University of British Columbia, Canada; and Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Israel (I.V.)
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16
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Vlodavsky I, Elkin M, Ilan N. Impact of heparanase and the tumor microenvironment on cancer metastasis and angiogenesis: basic aspects and clinical applications. Rambam Maimonides Med J 2011; 2:e0019. [PMID: 23908791 PMCID: PMC3678787 DOI: 10.5041/rmmj.10019] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) side chains at a limited number of sites, activity that is strongly implicated with cell invasion associated with cancer metastasis, a consequence of structural modification that loosens the extracellular matrix barrier. Heparanase activity is also implicated in neovascularization, inflammation, and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human heparanase cDNA 10 years ago enabled researchers to critically approve the notion that HS cleavage by heparanase is required for structural remodeling of the extracellular matrix (ECM), thereby facilitating cell invasion. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. The enzyme also releases angiogenic factors residing in the tumor microenvironment and thereby induces an angiogenic response in vivo. Heparanase up-regulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. These observations, the anticancerous effect of heparanase gene silencing and of heparanase-inhibiting molecules, as well as the unexpected identification of a single functional heparanase suggest that the enzyme is a promising target for anticancer drug development. Progress in the field expanded the scope of heparanase function and its significance in tumor progression and other pathologies such as inflammatory bowel disease and diabetic nephropathy. Notably, while heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that heparanase also functions in an enzymatic activity-independent manner. Thus, point-mutated inactive heparanase was noted to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. VEGF) and phosphorylation of selected Src substrates (i.e. EGF receptor). The concept of enzymatic activity-independent function of heparanase gained substantial support by elucidation of the heparanase C-terminus domain as the molecular determinant behind its signaling capacity and the identification of a human heparanase splice variant (T5) devoid of enzymatic activity, yet endowed with protumorigenic characteristics. Resolving the heparanase crystal structure will accelerate rational design of effective inhibitory molecules and neutralizing antibodies, paving the way for advanced clinical trials in patients with cancer and other diseases involving heparanase.
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Affiliation(s)
- Israel Vlodavsky
- Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel; and
- To whom correspondence should be addressed. E-mail:
| | - Michael Elkin
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Neta Ilan
- Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel; and
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17
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Domschke C, Schuetz F, Sommerfeldt N, Rom J, Scharf A, Sohn C, Schneeweiss A, Beckhove P. Effects of distant metastasis and peripheral CA 15-3 on the induction of spontaneous T cell responses in breast cancer patients. Cancer Immunol Immunother 2010; 59:479-86. [PMID: 19957084 PMCID: PMC11030215 DOI: 10.1007/s00262-009-0801-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Accepted: 11/18/2009] [Indexed: 11/26/2022]
Abstract
Tumor-specific memory T cells are detectable in the bone marrow (BM) of a majority of breast cancer patients. In vitro they can be reactivated to IFN-gamma producing, cytotoxic effector cells and reject autologous, xenotransplanted tumors in NOD/SCID mice after specific restimulation with autologous dendritic cells (DC). In this study, we demonstrate the presence of specific tumor-reactive BM memory T cells in altogether 56 out of 129 primarily operated breast cancer patients by short-term IFN-gamma EliSpot assays with unstimulated T cells and tumor antigen presenting, autologous DCs. We observed tumor-reactive BM memory T cells predominantly in patients with primarily metastatic disease (P = 0.011) or with increased concentrations of tumor marker CA 15-3 in the peripheral blood (P = 0.004), respectively. Memory T cell reactivity against HLA-A(*0201)-restricted peptides from the tumor-associated antigens MUC1, Hpa(16-24) and Hpa(183-191) was also detected particularly in patients with elevated peripheral CA 15-3 concentrations (P < 0.05). Altogether these data indicate that the systemic presence of tumor-derived antigens promotes an induction of tumor-specific cellular immune responses in the human BM.
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Affiliation(s)
- Christoph Domschke
- Department of Gynecology and Obstetrics, University Hospital of Heidelberg, Germany.
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18
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Escobar GA, Cheng AM, Moore EE, Johnson JL, Tannahill C, Baker HV, Moldawer LL, Banerjee A. Stored packed red blood cell transfusion up-regulates inflammatory gene expression in circulating leukocytes. Ann Surg 2007; 246:129-34. [PMID: 17592301 PMCID: PMC1899205 DOI: 10.1097/01.sla.0000264507.79859.f9] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
SUMMARY BACKGROUND DATA The transfusion of more than 6 units of packed red blood cells (PRBCs) within the first 12 hours of injury is the strongest independent predictor of multiple organ failure (MOF). This suggests that stored blood contains bioactive factors that may modify the immunoinflammatory response. METHODS To simulate postinjury major transfusions ex vivo, we obtained whole blood from 4 healthy adults and divided it into four 7-mL groups (I-IV). Group I was not diluted. Group II had 7 mL of 0.9% sterile saline (SS) added. Group III received 3.5 mL each of leuko-reduced stored PRBC and SS (simulating a major transfusion). Group IV received 3.5 mL each of SS and a hemoglobin-based oxygen carrier (PolyHeme) to evaluate the effects of hemoglobin alone. The hemoglobin content in groups III and IV was measured to be equal. Total leukocyte RNA was purified, and its gene array profiles were obtained. RESULTS Of the 56,475 oligonucleotide probe sets interrogated, 415 were statistically different (P < 0.001). Fourteen of the 415 probe sets were inflammatory-related. The PRBC group had a significantly different expression profile compared with the others and included up-regulation of the interleukin-8, toll-like receptor 4, cryropyrin, prostaglandin-endoperoxide synthase-2, and heparinase genes. CONCLUSIONS PRBCs activate inflammatory genes in circulating leukocytes, which may be central to the pathogenesis of the adverse inflammatory responses that lead to postinjury MOF.
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Affiliation(s)
- Guillermo A Escobar
- Department of Surgery, University of Colorado Health Science Center/Denver Health Medical Center, Denver, CO 80204, USA
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19
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Yang SM, Tang XD, Chen T, Xiong Z, Chen L, Cai YG, Fang DC. Heparanase: a new universal metastasis-associated antigen in the immunotherapy for the advanced cancers. Shijie Huaren Xiaohua Zazhi 2007; 15:849-854. [DOI: 10.11569/wcjd.v15.i8.849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Heparanase (Hpa) was an endo-β-D-glucuronidase that can cleave heparan sulfate proteoglycans (HSPGs) and has been implicated in tumor angiogenesis and metastasis. It has been reported that Hpa was expressed in almost all the advanced tumors, especially in metastatic tumors, and in contrast, down-regulation of Hpa could inhibit the metastasis of tumors. These results indicated that Hpa could serve as a new universal tumor-metastasis-associated antigen in the immunotherapy for the advanced tumors. Development of Hpa vaccine may establish a new method for the treatment of the advanced tumors. In this review, structure and functions of Hpa and its possibility as a new universal antigen in the immunotherapy of the advanced tumors were discussed.
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20
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Naomoto Y, Gunduz M, Takaoka M, Okawa T, Gunduz E, Nobuhisa T, Kobayashi M, Shirakawa Y, Yamatsuji T, Sonoda R, Matsuoka J, Tanaka N. Heparanase promotes angiogenesis through Cox-2 and HIF1α. Med Hypotheses 2007; 68:162-5. [PMID: 16890383 DOI: 10.1016/j.mehy.2006.03.055] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Accepted: 03/02/2006] [Indexed: 10/24/2022]
Abstract
Heparanase has been given attention for its role in the invasion and metastasis of various cancers for years. We have also investigated and reported the role of heparanase in several human cancers, including gastric, esophageal and colon carcinomas. Other than the critical role of heparanase in tumor invasion and metastasis, it is also believed that heparanase is involved in angiogenesis, another feature of tumor progression which is complicatedly mediated by many molecules, including cyclooxygenese-2 (Cox-2). Thus, our recent study elucidated a possible relationship of heparanase with Cox-2 upon tumor angiogenesis. Based upon our study, three major transcription factor binding sites containing NF-kappaB, NF-IL-6 and CRE sites seemed to have a compensative and cooperative role in heparanase-induced Cox-2 upregulation. On the other hand, tumor hypoxia often occurs in most tumors and Cox-2-induced HIF1alpha overexpression has recently been shown in various cancers. Here we believe that heparanase may also be involved in tumor hypoxia through the induction of HIFalpha either directly or indirectly through the Cox-2 pathway. This hypothesis indicates a possible novel function of heparanase and its link to HIF1alpha and Cox-2, and therefore this function would give us a clue about potential new strategies for cancer therapy.
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Affiliation(s)
- Yoshio Naomoto
- Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan.
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21
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Gao J, Su L, Qin R, Chang Q, Huang T, Feng Y. Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro. ACTA ACUST UNITED AC 2006; 26:72-4. [PMID: 16711012 DOI: 10.1007/bf02828042] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Extracellular matrix (ECM) degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase (HPSE) is an endoglycosidase that specifically degrades heparin sulfate proteoglycans (HSPG), a chief component of ECM. HPSE is not expressed in normal epithelial cells but can be detected in a variety of human carcinomas including pancreatic cancer. In the present study, human pancreatic cancer cell line Panc-1 was transfected with HPSE antisense oligodeoxynucleotide (AS-ODN) in vitro, then the inhibitory effect of AS-ODN on HPSE gene expression and invasive ability of Panc-1 cells in vitro was examined. The HPSE mRNA and protein expression of Panc-1 cells transfected with AS-ODN was significantly inhibited. However, there were no marked inhibitory effects in Panc-1 cells treated with nonsense oligodeoxynucleotide (NS-ODN). Moreover, a modified Boyden chamber assay demonstrated that transfection with HPSE AS-ODN significantly inhibited invasive potential of Panc-1 cells in vitro after AS-ODN transfection. This suggests that HPSE AS-ODN may contribute to the inhibition of HPSE mRNA and protein expression, and results in a decrease of the invasive ability of Panc-1 in vitro.
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Affiliation(s)
- Jun Gao
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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22
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Sommerfeldt N, Beckhove P, Ge Y, Schütz F, Choi C, Bucur M, Domschke C, Sohn C, Schneeweis A, Rom J, Pollmann D, Leucht D, Vlodavsky I, Schirrmacher V. Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res 2006; 66:7716-23. [PMID: 16885374 DOI: 10.1158/0008-5472.can-05-2363] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Increased expression and secretion of heparanase (Hpa) by tumor cells promotes tumor invasion through extracellular matrices, tissue destruction, angiogenesis, and metastasis. Here, we show the existence in breast cancer patients of Hpa-specific T lymphocytes by fluorescence-activated cell sorting flow cytometry using Hpa peptide-MHC class I tetramers. We furthermore show memory T-cell responses in a high proportion of breast cancer patients to Hpa-derived HLA-A2-restricted peptides, leading to production of IFN-gamma and to generation of antitumor CTLs lysing breast cancer cells. Such CTLs recognized endogenously processed respective Hpa peptides on Hpa-transfected and Hpa-expressing untransfected breast carcinoma cells. According to these results and to the fact that such cells were not found in healthy people, Hpa seems to be an attractive new tumor-associated antigen and its HLA-A2-restricted peptides ought to be good candidates for peptide vaccination to reactivate memory immune responses to invasive and metastatic cancer cells.
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Affiliation(s)
- Nora Sommerfeldt
- Department of Cellular Immunology, The German Cancer Research Center, D010 Im Neuenheimer Feld, 69120 Heidelberg, Germany
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Abstract
Metastatic growth is a selective, non-random process, which in the case of colorectal cancer, frequently occurs in the liver and is the major cause of cancer related death in these patients. This review summarises attempts to find biological and molecular markers of metastasis and their role in establishment of secondary tumours. Recent evidence suggests that liver metastases are phenotypically different to the primary from which they were derived and thus represent a separate disease entity.
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Affiliation(s)
- Nigel C Bird
- Liver Research Group, Clinical Sciences (South), Royal Hallamshire Hospital, Sheffield, United Kingdom.
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Abstract
Malignant pheochromocytoma is a rare disease with a high mortality. Surgical resection is the only effective treatment if extensive metastatic disease is not present. However, differentiating between benign and malignant pheochromocytoma is impossible in the absence of locoregional invasion or distant metastasis. This diagnostic dilemma has several drawbacks, including later detection and treatment of recurrence than if malignancy is determined at the original operation. With emerging molecular markers of malignant disease, optimal extent and approach for surgical treatment and appropriate extent of follow up could be established based on specific tumor behavior and the need for additional systemic therapy.
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Affiliation(s)
- Rasa Zarnegar
- Department of Surgery, University California San Francisco, Comprehensive Cancer Center at Mount Zion, Medical Center, 1600 Divisadero Street, Hellman Building, Room C347, San Francisco, CA 94143-1764, USA.
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Okawa T, Naomoto Y, Nobuhisa T, Takaoka M, Motoki T, Shirakawa Y, Yamatsuji T, Inoue H, Ouchida M, Gunduz M, Nakajima M, Tanaka N. Heparanase Is Involved in Angiogenesis in Esophageal Cancer through Induction of Cyclooxygenase-2. Clin Cancer Res 2005; 11:7995-8005. [PMID: 16299228 DOI: 10.1158/1078-0432.ccr-05-1103] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Both heparanase and cyclooxygenase-2 (COX-2) are thought to play critical roles for tumor malignancy, including angiogenesis, although it is unknown about their relationship with each other in cancer progression. We hypothesized that they may link to each other on tumor angiogenesis. EXPERIMENTAL DESIGN The expressions of heparanase and COX-2 in 77 primary human esophageal cancer tissues were assessed by immunohistochemistry to do statistical analysis for the correlation between their clinicopathologic features, microvessel density, and survival of those clinical cases. Human esophageal cancer cells were transduced with heparanase cDNA and used for reverse transcription-PCR and Western blot to determine the expression of heparanase and COX-2. COX-2 promoter vector and its deletion/mutation constructs were also used along with transduction of heparanase cDNA for luciferase assay. RESULTS Heparanase and COX-2 protein expression exhibited a similar pattern in esophageal tumor tissues, and their expression correlated with tumor malignancy and poor survival. Their expression also revealed a significant correlation with high intratumoral microvessel density. Up-regulation of COX-2 mRNA and protein was observed in esophageal cancer cells transfected with heparanase cDNA. COX-2 promoter was activated after heparanase cDNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-kappaB, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity. CONCLUSION Our results suggest that heparanase may play a novel role for COX-2-mediated tumor angiogenesis.
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Affiliation(s)
- Takaomi Okawa
- Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University, Okayama, Japan
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Han B, Liu J, Ma MJ, Zhao L. Clinicopathological significance of heparanase and basic fibroblast growth factor expression in human esophageal cancer. World J Gastroenterol 2005; 11:2188-92. [PMID: 15810091 PMCID: PMC4305794 DOI: 10.3748/wjg.v11.i14.2188] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Human heparanase is an endo-D-glucuronidase that degrades heparan sulfate/heparin and has been implicated in a variety of biological processes. The objective was to investigate the expression of heparanase (Hps) and basic fibroblast growth factor (bFGF) and their relationship to neoangiogenesis and metastasis of human esophageal carcinoma.
METHODS: Seventy-nine patients who had undergone esophageal resection for esophageal carcinoma without preoperative treatment were included in the present study. Immunohistochemistry was used to study the expression of Hps, bFGF and microvessel density (MVD) in 79 cases of esoph-ageal carcinoma. bFGF and Hps were quantitatively detected with immunohistochemistry in 79 cases of human esopha-geal carcinoma and 19 cases of adjacent normal human esophageal carcinoma. Cd34 was used to explore the MVD as a marker of endothelial cells.
RESULTS: Hps and bFGF expression in tumor tissue, being remarkably higher than that in normal esophageal tissue, were significantly correlated with clinicopathological features (depth of invasion, lymph-node metastasis and TNM stage) and MVD.
CONCLUSION: The results of this study suggest that the coexpression of Hps and bFGF plays a key role in angiogenesis, invasion and metastasis of esophageal carcinoma. Hps and bFGF may serve as a predictor of progression in esophageal carcinoma. The expression of heparanase in esophageal carcinoma enhances growth, invasion, and angiogenesis of the tumor, and bFGF seems to be a potent antigenic factor for esophageal carcinoma.
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Affiliation(s)
- Biao Han
- First Affiliated Hospital, Lanzhou, Medical College, Lanzhou 730000, Gansu Province, China
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27
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Ueno Y, Yamamoto M, Vlodavsky I, Pecker I, Ohshima K, Fukushima T. Decreased expression of heparanase in glioblastoma multiforme. J Neurosurg 2005; 102:513-21. [PMID: 15796387 DOI: 10.3171/jns.2005.102.3.0513] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object. The authors investigated the presence of endoglycosidase heparanase in human glioblastoma multiforme (GBM) and metastatic brain tumors as well as in healthy brain tissue to explore the relationship between the biological characteristics of GBM and the role of heparanase.
Methods. Heparanase messenger (m)RNA was almost undetectable in GBMs in vivo, whereas it was frequently seen in metastatic brain tumors according to results of reverse transcription—polymerase chain reaction (RT-PCR). Immunohistochemical analysis of paraffin-embedded tissue sections showed that neoplastic cells in metastatic brain tumors, especially in cells that invaded blood vessels, exhibit intense heparanase immunoreactivity. Heparanase was present in two highly invasive glioma cell lines, U87MG and U251MG, in vitro. These cell lines did not have metastatic capability, which was tested in an experimental pulmonary metastases model in mice. The activity of heparanase in these cell lines was almost the same as that in the highly metastatic melanoma cell line B16-F1. After nude mice were inoculated with U87MG cells, however, heparanase was no longer detected in subcutaneous or intracerebral experimental glioma in vivo based on results of immunohistochemical analysis. According to results of real-time quantitative PCR, there was a 10-fold increase in heparanase mRNA in U87MG glioma cells in vitro compared with that in experimental U87MG glioma tissue in vivo in nude mice.
Conclusions. These results indicate that the expression of heparanase was downregulated in GBM in vivo, which rarely metastasizes to distant organs outside the central nervous system. Heparanase is not implicated in the invasiveness of GBM to surrounding healthy brain tissue in vivo.
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Affiliation(s)
- Yushi Ueno
- Department of Neurosurgery, Fukuoka University School of Medicine, Fukuoka, Japan
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Wang Z, Xu H, Jiang L, Zhou X, Lu C, Zhang X. Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma. Mod Pathol 2005; 18:205-11. [PMID: 15475937 DOI: 10.1038/modpathol.3800282] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Tumor invasion and metastasis are the most common causes of death in gastric carcinoma. Human heparanase influences tumor invasiveness and angiogenesis. Analysis of its expression in gastric carcinoma has been hindered by our inability to procure pure cancer cells from heterogeneous tissue. In the present study, we analyzed heparanase expression in human primary and metastatic gastric carcinoma cells as well as in paired normal gastric epithelial cells by laser capture microdissection coupled with reverse transcription-polymerase chain reaction (RT-PCR). Tumor tissues, metastatic lymph nodes, and apparently uninvolved normal gastric tissues were collected from 30 patients who had undergone gastrectomy with radical lymph node dissection for gastric carcinoma without preoperative treatment. Bulk tissues and laser capture microdissected cell groups were separately subjected to RT-PCR analysis with heparanase-specific primers. For bulk tissues, heparanase-specific transcripts were detectable in all primary tumor tissues, metastatic lymph nodes, and almost all matching normal tissues. RT-PCR analysis after laser capture microdissection showed no detectable heparanase expression in matching normal epithelial cell groups. Of the laser capture microdissected primary gastric carcinoma cells, 47% (14/30) were heparanase positive. Expression was closely associated with greater tumor invasiveness, including Borrmann gross type and depth of wall infiltration. For metastatic cell groups dissected from lymph nodes, 95% showed clear heparanase expression. Furthermore, the extent of lymphatic spread was directly correlated to heparanase expression at the primary site. In conclusion, laser capture microdissection coupled with RT-PCR is a reliable approach for molecular analysis of heparanase expression in gastric carcinoma. Heparanase may facilitate invasion and metastasis of gastric carcinoma cells.
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Affiliation(s)
- Zhenning Wang
- The Research Center for Medical Genomics and MOH Key Laboratory of Cell Biology, Shenyang, PR China
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Bobek V, Kovarík J. Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother 2004; 58:213-9. [PMID: 15183845 DOI: 10.1016/j.biopha.2003.11.007] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2003] [Accepted: 11/10/2003] [Indexed: 02/06/2023] Open
Abstract
Experimental and clinical studies have shown an anticancer effect of anticoagulant drugs. The aim of this study is to review the mechanisms by which the common types of anticoagulants influence the primary tumor and metastatic processes of solid tumors. The review evaluates the interference of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and warfarin on the growth of primary tumors and on the development of metastases. The first part of the review evaluates the effect on the growth and development of primary tumors. Attention is paid to the interference with proliferation of cancer cells, tumor angiogenesis and to the interference with the immune system. The second part of the review describes the metastatic process and the effect of anticoagulants on the cell motility and cancer cell adhesion. The third part refers to the outcomes of clinical studies with anticoagulant treatment in patients with cancer. The problem of thromboembolic disease in patients with advanced cancer is also mentioned. The anticoagulants are more effective in inhibition of stages of the metastatic cascade than in the influence on primary tumors. They can interfere with tumor angiogenesis, immunity system, cancer cell motility and adhesion. The first clinical trials showed an effect on the development of primary tumors and survival of patients namely with lung cancer.
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Affiliation(s)
- Vladimir Bobek
- Department of Molecular Biology, Third Faculty of Medicine Charles University Prague, Ruska 87, 10034 Prague, Czech Republic.
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Chen XP, Liu YB, Rui J, Peng SY, Peng CH, Zhou ZY, Shi LH, Shen HW, Xu B. Heparanase mRNA expression and point mutation in hepatocellular carcinoma. World J Gastroenterol 2004; 10:2795-9. [PMID: 15334672 PMCID: PMC4572104 DOI: 10.3748/wjg.v10.i19.2795] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the expression of heparanase mRNA and point mutation in hepatocellular carcinoma (HCC).
METHODS: Reverse transcription polymerase chain reaction was used to measure the expression of heparanase mRNA in the primary tumor tissues and surrounding liver tissues of 33 HCC patients. T-A cloning and sequencing were used to detect whether there was any mutation in the amplified PCR products.
RESULTS: The expression of heparanase mRNA was positive in 16 primary tumor tissues of HCC, and the positive rate was 48.5%, which was significantly higher than that in the surrounding liver parenchyma (P < 0.01). The positive rate for heparanase gene in high-tendency to metastatic recurrence group (71.4%, 10/14) was obviously higher than that in low-tendency to metastatic recurrence group (31.6%, 6/19) (P = 0.023). The positive rate for heparanase gene in patients with metastatic recurrence during postoperative follow-up (78.6%, 11/14) was also significantly higher than that in those without metastatic recurrence (21.4%, 3/14) (P = 0.003). Sequence analysis of the HPA PCR products was made in 7 patients, and 2-point mutations were found in 4 patients, one of which was sense mutation, neither base insertion nor deletion was detected. The mutation rate was 57.1% (4/7).
CONCLUSION: The expression rate of heparanase mRNA increases in HCC, and HPA mRNA may be one of the reliable markers for the metastatic activity gained by the liver tumor cells and could be used clinically in predicting metastatic recurrence of HCC. Point mutation may be one of the causes for enhanced heparanase mRNA expression.
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Affiliation(s)
- Xiao-Peng Chen
- Department of Surgery, Affilicated Yijishan Hospital, Wannan Medical College, Wuhu 241001, Anhui Province, China.
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Abstract
A catecholamine-secreting tumor arising from the chromaffin cells of the sympathoadrenal system was first termed pheochromocytoma by Poll in 1905. The term refers to the dysky (pheo) color (chromo) of the cut surface of the tumor when exposed to dichromate. Pheochromocytomas most commonly arise from the adrenal medulla. Extraadrenally located pheochromocytomas are called paragangliomas, and arise from the paraganglion system. An adrenal pheochromocytoma is usually a rounded, gray-white, firm tumor 3 to 5 cm in diameter. When larger, they can adhere to adjacent structures, although still not metastasizing. Most pheochromocytomas are benign. However, approximately 10% of these tumors metastasize. It is almost impossible to differentiate a benign from a malignant tumor only by histological criteria. Classically only metastasized tumors are considered malignant for certain. Many attempts have been made to find markers that would predict the future behavior of an unmetastasized pheochromocytoma. In this overview of malignancy in pheochromocytomas, different steps of the tumorigenesis and several markers associated with them are discussed.
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Affiliation(s)
- Kaisa Salmenkivi
- Department of Pathology, Haartman Institute, University of Helsinki and HUCH Laboratory Diagnostics, Helsinki University Central Hospital, Helsinki, Finland.
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Mikami S, Ohashi K, Katsube KI, Nemoto T, Nakajima M, Okada Y. Coexpression of heparanase, basic fibroblast growth factor and vascular endothelial growth factor in human esophageal carcinomas. Pathol Int 2004; 54:556-63. [PMID: 15260846 DOI: 10.1111/j.1440-1827.2004.01664.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Heparan sulfate (HS), which is degraded by heparanase, plays an important role in cell adhesion, insolubility of the extracellular matrix (ECM) and as a reservoir for various growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). In the present study, we examined the immunohistochemical expression of heparanase, bFGF and VEGF, and evaluated the correlation between their expression and microvessel density (MVD) in human esophageal carcinomas. Heparanase, bFGF and VEGF were immunolocalized predominantly to the carcinoma cells, but they were also localized to the endothelial cells of microvessels near the carcinoma cell nests. In carcinomas with invasion of the muscular layer or adventitia, heparanase staining was stronger at the invasive areas of carcinomas than the intraepithelial spread. Expression of heparanase and bFGF and the degree of MVD were associated with tumor invasion, lymph node metastasis and pathological stages. Cases with positive staining for heparanase, bFGF or VEGF tended to have a higher MVD than those without staining, and carcinomas with concomitant expression of heparanase, bFGF and VEGF showed the highest MVD. The level of heparanase mRNA expression was directly correlated with the MVD. In addition, heparanase-positive cases had a higher positive ratio of bFGF and VEGF compared with the heparanase-negative cases. These data suggest the possibility that heparanase may contribute to not only cancer cell invasion but also angiogenesis probably through degradation of HS in the ECM and release of bFGF and VEGF from the HS-containing ECM.
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Affiliation(s)
- Shuji Mikami
- Division of Diagnostic Pathology, School of Medicine, Keio University, Tokyo, Japan
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Takahashi H, Ebihara S, Okazaki T, Suzuki S, Asada M, Kubo H, Sasaki H. Clinical significance of heparanase activity in primary resected non-small cell lung cancer. Lung Cancer 2004; 45:207-14. [PMID: 15246192 DOI: 10.1016/j.lungcan.2004.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2003] [Revised: 01/30/2004] [Accepted: 02/05/2004] [Indexed: 10/26/2022]
Abstract
Clinicopathological significances of heparanase activity in non-small cell lung cancer (NSCLC) were investigated by analyzing 76 resected specimens of NSCLC. Heparanase activities in NSCLC were significantly higher than non-cancerous lung tissues (P < 0.0001). The heparanase activities of NSCLC were significantly higher in larger diameter tumors (P = 0.0141) or with metastasis to ipsilateral mediastinal lymph nodes (P = 0.0004). The activities of heparanase in primary tumors were increased significantly according to the pathological stage of the progression of the disease (P =0.0009). Among the clinicopathological parameters, histological cell type and evidence of ipsilateral lymph node metastasis showed a significant association with elevated heparanase activities, whereas age, degree of differentiation and tumor diameter did not. Kaplan-Meier curves for overall and disease-free survival demonstrated a significant difference between patients with elevated and non-elevated heparanase activity by log-rank test (P = 0.0145 and 0.0002, respectively). Multivariate analysis showed heparanase activity was an independent factor to influence disease-free survival in our study. These results suggest that heparanase activity could be used as a prognostic indicator for postoperative patients with NSCLC and heparanase might be a promising molecular target for treatment of NSCLC.
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Affiliation(s)
- Hidenori Takahashi
- Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Seiryo-machi 1-1, Aoba-ku, Sendai 980-8574, Japan
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Yuan K, Hong TM, Chen JJW, Tsai WH, Lin MT. Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis. Blood 2004; 104:1025-33. [PMID: 15126321 DOI: 10.1182/blood-2003-09-3334] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
EphrinB2 and EphB4, its cognate receptor, are important in the vascular development of the mouse embryo. Their roles in human inflammatory angiogenesis, however, are not well understood. By examining hyperinflammatory lesions, we saw that ephrinB2 was predominantly expressed in macrophage-like cells and EphB4 in small venules. Because macrophages usually transmigrate through postcapillary venules during inflammation, we wanted to explore the downstream effects of EphB4 after binding to ephrinB2. By using cDNA microarray technique and following reverse transcriptase-polymerase chain reaction (RT-PCR), we found that syntenin and syndecan-1 were up-regulated in EphB4-positive endothelial cells dose dependently and time dependently after stimulation with preclustered ephrinB2. In vitro, ephrinB2 suppressed the angiogenic effects of basic fibroblast growth factor (bFGF) on EphB4-positive endothelial cells, partially due to syndecan-1's competition with fibroblast growth factor receptor (FGFR) for bFGF. However, ephrinB2 exhibited angiogenic effects in vivo, possibly due to an inflammation-associated enzyme-heparanase. The enzymes could convert the inhibitory effect of ephrinB2 on EphB4-positive endothelial cells to an activating effect by removing poorly sulfated side chains of up-regulated syndecan-1 ectodomain. Depending on the presence of heparanases, the roles of syndecan-1 may be opposite in different physiological settings.
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Affiliation(s)
- Kuo Yuan
- Institute of Medical Sciences, Tzu Chi University, No. 701, Jung-Yang Rd, Section 3, Hualien, Taiwan 970
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:439-442. [DOI: 10.11569/wcjd.v12.i2.439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/27/2023] Open
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Cai YG, Fang DC, Yang SM, Luo YH, Yang MH, Wang DX. Construction and identification of sense and antisense human heparanase adenovirus expression vector. Shijie Huaren Xiaohua Zazhi 2004; 12:336-338. [DOI: 10.11569/wcjd.v12.i2.336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct an adenovirus expressing vector of sense and antisense human heparanase gene.
METHODS: The human heparanase cDNA fragment contained in the pcDNA3-hpa vector was cloned into the adenovirus expressing vector pDC315 in cis-direction or trans-direction using DNA recombinant technology. The recombinant vectors were identified by digestion of BamH I. The sense recombinant vector was further identified by DNA sequencing.
RESULTS: After digested by BamH I, two fragments which lengthened 4.3 and 1.4 kb were formed in sense recombinant vector (pDC315-sHpa), while two fragments which lengthened 5.1 kb and 0.4 kb were formed in antisense vector (pDC315-aHpa). Electrophoresis results were completely coincident with theoretical calculation. pDC315-sHpa DNA sequence was identical to the heparanase sequence published in the Gene Bank.
CONCLUSION: The sense and antisense human heparanase adenovirus expressing vectors are successfully constructed.
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Reiland J, Sanderson RD, Waguespack M, Barker SA, Long R, Carson DD, Marchetti D. Heparanase Degrades Syndecan-1 and Perlecan Heparan Sulfate. J Biol Chem 2004; 279:8047-55. [PMID: 14630925 DOI: 10.1074/jbc.m304872200] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Heparanase (HPSE-1) is involved in the degradation of both cell-surface and extracellular matrix (ECM) heparan sulfate (HS) in normal and neoplastic tissues. Degradation of heparan sulfate proteoglycans (HSPG) in mammalian cells is dependent upon the enzymatic activity of HPSE-1, an endo-beta-d-glucuronidase, which cleaves HS using a specific endoglycosidic hydrolysis rather than an eliminase type of action. Elevated HPSE-1 levels are associated with metastatic cancers, directly implicating HPSE-1 in tumor progression. The mechanism of HPSE-1 action to promote tumor progression may involve multiple substrates because HS is present on both cell-surface and ECM proteoglycans. However, the specific targets of HPSE-1 action are not known. Of particular interest is the relationship between HPSE-1 and HSPG, known for their involvement in tumor progression. Syndecan-1, an HSPG, is ubiquitously expressed at the cell surface, and its role in cancer progression may depend upon its degradation. Conversely, another HSPG, perlecan, is an important component of basement membranes and ECM, which can promote invasive behavior. Down-regulation of perlecan expression suppresses the invasive behavior of neoplastic cells in vitro and inhibits tumor growth and angiogenesis in vivo. In this work we demonstrate the following. 1) HPSE-1 cleaves HS present on the cell surface of metastatic melanoma cells. 2) HPSE-1 specifically degrades HS chains of purified syndecan-1 or perlecan HS. 3) Syndecan-1 does not directly inhibit HPSE-1 enzymatic activity. 4) The presence of exogenous syndecan-1 inhibits HPSE-1-mediated invasive behavior of melanoma cells by in vitro chemoinvasion assays. 5) Inhibition of HPSE-1-induced invasion requires syndecan-1 HS chains. These results demonstrate that cell-surface syndecan-1 and ECM perlecan are degradative targets of HPSE-1, and syndecan-1 regulates HPSE-1 biological activity. This suggest that expression of syndecan-1 on the melanoma cell surface and its degradation by HPSE-1 are important determinants in the control of tumor cell invasion and metastasis.
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Affiliation(s)
- Jane Reiland
- Department of Comparative Biomedical Sciences-SVM, Louisiana State University, Baton Rouge, Louisiana 70803, USA
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Sato T, Yamaguchi A, Goi T, Hirono Y, Takeuchi K, Katayama K, Matsukawa S. Heparanase expression in human colorectal cancer and its relationship to tumor angiogenesis, hematogenous metastasis, and prognosis. J Surg Oncol 2004; 87:174-81. [PMID: 15334632 DOI: 10.1002/jso.20097] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Heparanase is considered to play an important role in tumor invasion and hematogenous metastasis. The aim of this study was to determine the expression of heparanase in colorectal cancer to evaluate its prognostic value. METHODS We analyzed heparanase mRNA derived from 130 colorectal cancer patients by reverse transcription polymerase chain reaction (PCR), compared its expression with clinicopathologic factors, and performed statistical analysis. To investigate the relationship between heparanase expression and tumor angiogenesis, 81 primary colorectal tumors were immunostained by use of a monoclonal anti-CD34 antibody. RESULTS Thirty three of 130 cancer tissues overexpressed heparanase. There were significant correlations between heparanase expression and serosal invasion, venous invasion, and liver metastasis. Multivariate analyzes revealed that heparanase mRNA overexpression was a significant independent risk factor for hematogenous metastasis in colorectal cancer. Among 104 patients who underwent curative resection, heparanase expression correlated with a high recurrence. The 5-year survival rate was 84.6% for patients with heparanase negative tumors, and 47.7% for those with heparanase overexpression; these differences between two groups of patients were significant. In multivariate analysis using the Cox regression model, heparanese expression emerged as an independent prognostic indicator. Moreover, the tumor angiogenesis of heparanase-positive tumors determined with a monoclonal anti-CD34 antibody was significantly higher than that of heparanase-negative tumors. CONCLUSIONS These results indicated that Heparanase expression may be an important role in invasion and hematogenous metastasis, and may be a biologic marker of prognostic significance in colorectal cancer patients.
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Affiliation(s)
- Tomohiro Sato
- First Department of Surgery, University of Fukui, Matsuoka-cho, Yoshida-gun, Fukui, Japan
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Yang YJ, Zhang YL, Li X, Dan HL, Lai ZS, Wang JD, Wang QY, Cui HH, Sun Y, Wang YD. Contribution of eIF-4E inhibition to the expression and activity of heparanase in human colon adenocarcinoma cell line: LS-174T. World J Gastroenterol 2003; 9:1707-12. [PMID: 12918105 PMCID: PMC4611528 DOI: 10.3748/wjg.v9.i8.1707] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Heparanase degrades heparan sulfate proteoglycans (HSPGs) and is a critical mediator of tumor metastasis and angiogenesis. Recently, it has been cloned as a single gene family and found to be a potential target for antimetastasis drugs. However, the molecular basis for the regulation of heparanase expression is still not quite clear. The aim of this study was to determine whether the expression of eukaryotic initiation factor 4E (eIF-4E) correlated with the heparanase level in tumor cells and to explore the correlation between heparanase expression and metastatic potential of LS-174T cells.
METHODS: A 20-mer antisense s-oligodeoxynucleotide (asODN) targeted against the translation start site of eIF-4E mRNA was introduced into LS-174T cells by lipid-mediated DNA-transfection. eIF-4E protein and mRNA levels were detected by Western blot analysis and RT-PCR, respectively. Heparanase activity was defined as the ability to degrade high molecular weight (40-100 kDa) radiolabeled HS (heparan sulfate) substrate into low molecular weight (5-15 kDa) HS fragments that could be differentiated by gel filtration chromatography. The invasive potential of tumor cell in vitro was observed by using a Matrigel invasion assay system.
RESULTS: The 20-mer asODN against eIF-4E specifically and significantly inhibited eIF-4E expression at both transcriptional and translational levels. As a result, the expression and activity of heparanase were effectively retarded and the decreased activity of heparanase resulted in the decreased invasive potential of LS-174T.
CONCLUSION: eIF-4E is involved in the regulation of heparanase production in colon adenocarcinoma cell line LS-174T, and its critical function makes it a particularly interesting target for heparanase regulation. This targeting strategy in antisense chemistry may have practical applications in experimental or clinical anti-metastatic gene therapy of human colorectal carcinoma.
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Affiliation(s)
- Yu-Jie Yang
- Chinese PLA Institute of Digestive Disease, Nanfang Hospital, First Military Medical University, Guangzhou 510515, Guangdong Province, China.
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Lu WC, Liu YN, Kang BB, Chen JH. Trans-activation of heparanase promoter by ETS transcription factors. Oncogene 2003; 22:919-23. [PMID: 12584571 DOI: 10.1038/sj.onc.1206201] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The remodeling of extracellular matrix (ECM) is an important process required for cancer cells to turn into invasive and metastatic cancer cells. To dissolve the protein components of ECM, matrix metalloproteinases are some of the essential enzymes. Another ECM remodeling enzyme is the heparanase (Hpa) that digests the heparin sulfate component of the matrix. In metastatic cancer cells the Hpa gene is upregulated. To investigate the mechanism of why Hpa was upregulated in metastatic cancer cells, the regulatory sequence of heparanase gene was isolated and its function analysed in metastatic breast cancer cells. We found there are four ETS transcription factor binding sites. Two of them flanking the transcription initiation of the Hpa gene are nonfunctional, whereas two others are highly functional and responded to exogenously added ETS transcription factors. Mutation of these two ETS binding sites abolished the transcriptional activation of Hpa promoter by ETS transcription factors. Among four transcription factors tested (ETS1, ETS2, PEA3, and ER81), ETS1 and ETS2 are more potent in transactivating the human Hpa gene. Furthermore, dominant-negative ETS transcription factors failed to transactivate Hpa promoter and could abrogate the function of wild-type transcription factor in transactivation activity of ETS transcription factors on the Hpa promoter. These results suggest that ETS transcription factors play an important role in tumor invasion and metastasis by modulating the remodeling of ECM.
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Affiliation(s)
- W C Lu
- Graduate Institute of Human Genetics, Tzu Chi University, Hualien, Taiwan
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Quiros RM, Kim AW, Maxhimer J, Gattuso P, Xu X, Prinz RA. Differential heparanase-1 expression in malignant and benign pheochromocytomas. J Surg Res 2002; 108:44-50. [PMID: 12443714 DOI: 10.1006/jsre.2002.6451] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Extracellular matrix (ECM) degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase-1 (HPR) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a chief component of the ECM. Previous studies have demonstrated HPR expression in various malignancies and that there is differential HPR expression between benign and malignant tumors. Currently, there is no technique that can reliably predict the malignant behavior of some pheochromocytomas. This study tests whether HPR is differentially expressed in malignant and benign pheochromocytomas. METHODS Paraffin-embedded specimens from 29 pheochromocytomas were evaluated. The tissues were collected from surgical specimens over a 10-year period from 26 patients (8 males, 18 females) with a mean age of 47 years (range 19-78 years, median 47 years). One female patient underwent 3 separate operations for malignant pheochromocytoma and thus provided 3 specimens. Another female patient had both the primary tumor and a liver metastasis processed, and therefore provided 2 specimens. Patient charts and pathology reports were reviewed to classify the pheochromocytomas as either benign or malignant. Based on clinical behavior and/or pathological evidence of metastasis or invasion into surrounding tissues, 10 specimens were malignant and 19 had benign behavior. As a control, normal adrenal tissue from 3 nephrectomy specimens was included in the study, as was tissue from 1 adrenocortical adenoma. All 33 specimens were tested for HPR gene expression by in situ hybridization (ISH) with an antisense RNA probe and immunohistochemistry (IHC) with an anti-HPR antibody. Statistical analysis was done using the chi(2) test of proportions to determine if HPR expression correlated with malignancy using ISH, IHC, or both tests together. RESULTS Using ISH, the percentage of HPR expression in the malignant pheochromocytomas was 50% while HPR expression in the benign tumors was 21% (P = 0.11). Using IHC, the percentage of HPR expression in the malignant pheochromocytomas was 80% while HPR expression in the benign tumors was 32% (P = 0.01). Considering both tests cumulatively, all 10 malignant pheochromocytomas stained positive for HPR by ISH and IHC, while only 37% of the benign tumors were positive for HPR expression (P = 0.001). The one adrenal adenoma and the 3 normal adrenal glands processed stained negative for HPR expression by both ISH and IHC. CONCLUSIONS HPR expression is higher in malignant pheochromocytomas than in benign pheochromocytomas or normal tissue. HPR may contribute to the invasive characteristics of malignant pheochromocytomas and might be used as a marker to distinguish malignant from benign pheochromocytomas. HPR expression might also be used as a prognostic tool in guiding long-term patient follow-up.
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Affiliation(s)
- Roderick M Quiros
- Department of General Surgery, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612-3833, USA
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Jiang P, Kumar A, Parrillo JE, Dempsey LA, Platt JL, Prinz RA, Xu X. Cloning and characterization of the human heparanase-1 (HPR1) gene promoter: role of GA-binding protein and Sp1 in regulating HPR1 basal promoter activity. J Biol Chem 2002; 277:8989-98. [PMID: 11779847 DOI: 10.1074/jbc.m105682200] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Heparanase-1 (HPR1) is an endoglycosidase that specifically degrades the heparan sulfate chains of proteoglycan, a component of blood vessel walls and the extracellular matrix. Recent studies demonstrated that HPR1 expression is increased in a variety of malignancies and may play a critical role in tumor metastases. The HPR1 gene and its genomic structure have been recently cloned and characterized. To understand the mechanisms of HPR1 gene expression and regulation, we first mapped the transcription start site of the HPR1 gene and found that HPR1 mRNA was transcribed from the nucleotide position 101 bp upstream of the ATG codon. A 3.5-kb promoter region of the HPR1 gene was cloned. Sequence analysis revealed that the TATA-less, GC-rich promoter of the HPR1 gene belongs to the family of housekeeping genes. This 3.5-kb promoter region exhibited strong promoter activity in two thyroid tumor cell lines. Truncation analysis of the HPR1 promoter identified a minimal 0.3-kb region that had strong basal promoter activity. Truncation and mutational analysis of the HPR1 promoter revealed three Sp1 sites and four Ets-relevant elements (ERE) significantly contributing to basal HPR1 promoter activity. Binding to the Sp1 sites by Sp1 and to the ERE sites by GA-binding protein (GABP) was confirmed by electrophoretic mobility shift assay and competition and supershift electrophoretic mobility shift assays. Cotransfection of Sp- and GABP-deficient Drosophila SL-2 cells with the HPR1 promoter-driven luciferase construct plus the expression vector encoding the Sp1, Sp3, or GABP gene induced luciferase gene expression. Mutation or truncation of the Sp1 or ERE sites reduced luciferase expression in both SL-2 cells and thyroid tumor cell lines. Coexpression of GABPalpha/beta and Sp1 or Sp3 further increased luciferase reporter gene expression. Our results collectively suggest that Sp1 cooperates with GABP to regulate HPR1 promoter activity.
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Affiliation(s)
- Ping Jiang
- Department of General Surgery and the Division of Cardiovascular Diseases and Critical Care, Department of Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA
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Kim AW, Xu X, Hollinger EF, Gattuso P, Godellas CV, Prinz RA. Human heparanase-1 gene expression in pancreatic adenocarcinoma. J Gastrointest Surg 2002; 6:167-72. [PMID: 11992801 DOI: 10.1016/s1091-255x(01)00087-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Extracellular matrix degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase-1 (HPR1) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a chief component of the extracellular matrix. HPR1 is not expressed in normal epithelial cells but can be detected in a variety of malignancies. In the present study, we examined HPR1 expression in pancreatic cancer by using in situ hybridization and tested whether HPR1 expression correlated with any clinicopathlogic parameters. HPR1 was not detected in the ductal cells of normal pancreas samples obtained from 10 patients at autopsy. However, HPR1 was detected in 77 (78%) of 99 pancreatic adenocarcinomas. Among them, 69 (78%) of 89 primary pancreatic adenocarcinomas and 8 (80%) of the 10 metastases were HPR1 positive. Age, sex, tumor stage, and lymph node status were not predictive of HPR1 expression. Log-rank test of the Kaplan-Meier survival curves revealed that HPR1 expression in early-stage tumors was associated with decreased survival. HPR1 expression was frequent in pancreatic adenocarcinomas and was associated with decreased survival in early-stage tumors. This suggests that HPR1 may contribute to the highly invasive and early metastatic behavior of pancreatic cancer.
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Affiliation(s)
- Anthony W Kim
- Department of General Surgery, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA
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Liu D, Shriver Z, Venkataraman G, El Shabrawi Y, Sasisekharan R. Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis. Proc Natl Acad Sci U S A 2002; 99:568-73. [PMID: 11805315 PMCID: PMC117346 DOI: 10.1073/pnas.012578299] [Citation(s) in RCA: 186] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Heparan sulfate glycosaminoglycans, present at the cell surface and in the extracellular matrix that surrounds cells, are important mediators of complex biological processes. Furthermore, it is now apparent that cells dynamically regulate the structure of their heparan sulfate "coat" to differentially regulate extracellular signals. In the present study, the importance of sequence information contained within tumor cell-surface heparan sulfate was investigated. Herein, we demonstrate that the heparan sulfate glycosaminoglycan coat present on tumor cells contains bioactive sequences that impinge on tumor-cell growth and metastasis. Importantly, we find that growth promoting as well as growth inhibiting sequences are contained within the polysaccharide coat. Furthermore, we find that the dynamic balance between these distinct polysaccharide populations regulates specific intracellular signal-transduction pathways. This study not only provides a framework for the development of polysaccharide-based anti-cancer molecules but also underscores the importance of understanding a cell's polysaccharide array in addition to its protein complement, to understand how genotype translates to phenotype in this post-genomic age.
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Affiliation(s)
- Dongfang Liu
- Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Marchetti D, Nicolson GL. Human heparanase: a molecular determinant of brain metastasis. ADVANCES IN ENZYME REGULATION 2001; 41:343-59. [PMID: 11384754 DOI: 10.1016/s0065-2571(00)00016-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- D Marchetti
- Department of Neurosurgery, The University of Texas-Houston Health Science Center, Houston TX 77030, USA
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Norrby K. 2.5 kDa and 5.0 kDa heparin fragments specifically inhibit microvessel sprouting and network formation in VEGF165-mediated mammalian angiogenesis. Int J Exp Pathol 2000; 81:191-8. [PMID: 10971740 PMCID: PMC2517726 DOI: 10.1046/j.1365-2613.2000.00150.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Tumour growth is angiogenesis dependent. Thrombosis and thromboembolism are very common in cancer patients. These patients are often treated with heparin as an anti-coagulant. Many tumour angiogens, including VEGF165, and endogenous anti-angiogenesis factors bind heparin tightly. Using the non-surgical mesenteric-window angiogenesis assay, we studied in detail the systemic effect of heparin fractions with a mean MW of 2.5, 5.0 and 16.4 kDa on the microvessel sprouting and network formation in angiogenesis mediated by VEGF165 in rats. The microvessel network was assessed objectively in terms of the number and lengths of segments (the distance between two successive branching points), the number of branching points, the degree of tortuosity, the index of interconnecting loop formation, the index of intersection, as well as the number and lengths of sprouts. Compared with the saline control, the 2.5 kDa fraction significantly shortened the microvessel sprouts and the microvessel segments but increased the microvessel tortuosity in statistical terms; the 5.0 kDa fraction statistically significantly shortened the sprouts, decreased the number of segments and the number of microvessel branching points; whereas the 16.4 kDa fraction statistically significantly elongated the longest segments. Moreover, statistically significant differences were found between the three heparin fractions in terms of microvessel tortuosity (2.5 vs. 16.4 kDa), index of loop formation (5.0 vs. 2.5 + 16.4 kDa) and index of intersection (5.0 vs. 16.4 kDa). These findings demonstrate that heparin fragments size-specifically inhibit microvessel sprouting and network formation in VEGF165-mediated angiogenesis. As VEGF165 is a potent angiogen in human tumours, we suggest that heparin enriched in 2.5 kDa species and 5.0 kDa species especially should be exploited as a combined anti-coagulant and specific adjuvant anti-angiogenic agent in cancer patients who require anti-coagulant therapy.
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Affiliation(s)
- K Norrby
- Department of Pathology, Sahlgrenska University Hospital, Göteborg University, Sweden.
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Fairbanks MB, Mildner AM, Leone JW, Cavey GS, Mathews WR, Drong RF, Slightom JL, Bienkowski MJ, Smith CW, Bannow CA, Heinrikson RL. Processing of the human heparanase precursor and evidence that the active enzyme is a heterodimer. J Biol Chem 1999; 274:29587-90. [PMID: 10514423 DOI: 10.1074/jbc.274.42.29587] [Citation(s) in RCA: 152] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Human platelet heparanase has been purified to homogeneity and shown to consist of two, non-covalently associated polypeptide chains of molecular masses 50 and 8 kDa. Protein sequencing provided the basis for determination of the full-length cDNA for this novel protein. Based upon this information and results from protein analysis and mass spectrometry, we propose a scheme to define the structural organization of heparanase in relation to its precursor forms, proheparanase and pre-proheparanase. The 8- and 50-kDa chains which make up the active enzyme reside, respectively, at the NH(2)- and COOH-terminal regions of the inactive precursor, proheparanase. The heparanase heterodimer is produced by excision and loss of an internal linking segment. This paper is the first to suggest that human heparanase is a two-chain enzyme.
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Affiliation(s)
- M B Fairbanks
- Protein Science Research Operations, Kalamazoo, Michigan 49001, USA
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