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1
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Wang Y, Wang T, Cao Y, Qiao X, Han X, Liu ZP. TopMarker: Computational screening biomarkers of hepatocellular carcinoma from transcriptome and interactome based on differential network topological parameters. Comput Biol Chem 2024; 112:108166. [PMID: 39111022 DOI: 10.1016/j.compbiolchem.2024.108166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/23/2024] [Accepted: 07/31/2024] [Indexed: 09/13/2024]
Abstract
Identifying diagnostic biomarkers for cancer is crucial in the field of personalized medicine. The available transcriptome and interactome provide unprecedented opportunities and challenges for biomarker screening. From a systematic perspective, network-based medicine methods provide alternative approaches to organizing the available high-throughput omics data for deciphering molecular interactions and their associations with phenotypic states. In this work, we propose a bioinformatics strategy named TopMarker for discovering diagnostic biomarkers by comparing the network topology differences in control and disease samples. Specifically, we build up gene-gene interaction networks in the two states of control and disease respectively. The network rewiring status across the two networks results in differential network topologies reflecting dynamics and changes in normal samples when compared with those in disease. Thus, we identify the potential biomarker genes with differential network topological parameters between the control and disease gene networks. For a proof-of-concept study, we introduce the computational pipeline of biomarker discovery in hepatocellular carcinoma (HCC). We prove the effectiveness of the proposed TopMarker method using these candidate biomarkers in classifying HCC samples and validate its signature capability across numerous independent datasets. We also compare the discriminant power of biomarker genes identified by TopMarker with those identified by other baseline methods. The higher classification performances and functional implications indicate the advantages of our proposed method for discovering biomarkers from differential network topology.
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Affiliation(s)
- Yanqiu Wang
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China
| | - Tong Wang
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China
| | - Yi Cao
- Center for Biomedical Engineering, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xu Qiao
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China
| | - Xianhua Han
- Faculty of Science, Yamaguchi University, Yamaguchi 753-8511, Japan
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China.
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2
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Xia L, Feng M, Ren Y, Hao X, Jiao Q, Xu Q, Wang Y, Wang Q, Gong N. DSE inhibits melanoma progression by regulating tumor immune cell infiltration and VCAN. Cell Death Discov 2023; 9:373. [PMID: 37833287 PMCID: PMC10576081 DOI: 10.1038/s41420-023-01676-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/23/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
Dermatan sulfate epimerase (DSE) is a C5 epiminase that plays a key role in converting chondroitin sulfate into dermal sulfate. DSE is often upregulated during carcinogenesis of some types of cancer and can regulate growth factor signaling in cancer cells. However, the expression and function of DSE in human melanoma have not been reported. In this study, we investigated the influence of tumor-derived DSE in melanoma progression and the potential mechanism of their action. First, proteomic analysis of collected melanoma tissues revealed that DSE was significantly down-regulated in melanoma tissues. DSE silenced or overexpressed melanoma cells were constructed to detect the effect of DSE on melanoma cells, and it was found that the up-regulation of DSE significantly inhibited the proliferation, migration and invasion of melanoma cells. Data analysis and flow cytometry were used to evaluate the immune subpopulations in tumors, and it was found that the high expression of DSE was closely related to the invasion of killer immune cells. Mechanistically, DSE promoted the expression of VCAN, which inhibited the biological activity of melanoma cells. Together, these results suggest that DSE is downregulated in melanoma tissues, and that high expression of DSE can promote melanoma progression by inducing immune cell infiltration and VCAN expression.
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Affiliation(s)
- Lin Xia
- Department of Plastic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Maoxiao Feng
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, China
| | - Xiaodong Hao
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Qinlian Jiao
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - QinChen Xu
- Department of Clinical Laboratory, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Qin Wang
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, China.
| | - Ningji Gong
- Department of Emergency, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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3
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Yang H, Wang L. Heparan sulfate proteoglycans in cancer: Pathogenesis and therapeutic potential. Adv Cancer Res 2023; 157:251-291. [PMID: 36725112 DOI: 10.1016/bs.acr.2022.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The heparan sulfate proteoglycans (HSPGs) are glycoproteins that consist of a proteoglycan "core" protein and covalently attached heparan sulfate (HS) chain. HSPGs are ubiquitously expressed in mammalian cells on the cell surface and in the extracellular matrix (ECM) and secretory vesicles. Within HSPGs, the protein cores determine when and where HSPG expression takes place, and the HS chains mediate most of HSPG's biological roles through binding various protein ligands, including cytokines, chemokines, growth factors and receptors, morphogens, proteases, protease inhibitors, and ECM proteins. Through these interactions, HSPGs modulate cell proliferation, adhesion, migration, invasion, and angiogenesis to display essential functions in physiology and pathology. Under physiological conditions, the expression and localization of HSPGs are finely regulated to orchestrate their physiological functions, and this is disrupted in cancer. The HSPG dysregulation elicits multiple oncogenic signaling, including growth factor signaling, ECM and Integrin signaling, chemokine and immune signaling, cancer stem cell, cell differentiation, apoptosis, and senescence, to prompt cell transformation, proliferation, tumor invasion and metastasis, tumor angiogenesis and inflammation, and immunotolerance. These oncogenic roles make HSPGs an attractive pharmacological target for anti-cancer therapy. Several therapeutic strategies have been under development, including anti-HSPG antibodies, peptides and HS mimetics, synthetic xylosides, and heparinase inhibitors, and shown promising anti-cancer efficacy. Therefore, much progress has been made in this line of study. However, it needs to bear in mind that the roles of HSPGs in cancer can be either oncogenic or tumor-suppressive, depending on the HSPG and the cancer cell type with the underlying mechanisms that remain obscure. Further studies need to address these to fill the knowledge gap and rationalize more efficient therapeutic targeting.
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Affiliation(s)
- Hua Yang
- Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Lianchun Wang
- Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States; Bryd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.
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4
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Marques C, Reis CA, Vivès RR, Magalhães A. Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression. Front Oncol 2021; 11:778752. [PMID: 34858858 PMCID: PMC8632541 DOI: 10.3389/fonc.2021.778752] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/15/2021] [Indexed: 12/17/2022] Open
Abstract
Heparan Sulfate Proteoglycans (HSPGs) are important cell surface and Extracellular Matrix (ECM) maestros involved in the orchestration of multiple cellular events in physiology and pathology. These glycoconjugates bind to various bioactive proteins via their Heparan Sulfate (HS) chains, but also through the protein backbone, and function as scaffolds for protein-protein interactions, modulating extracellular ligand gradients, cell signalling networks and cell-cell/cell-ECM interactions. The structural features of HS chains, including length and sulfation patterns, are crucial for the biological roles displayed by HSPGs, as these features determine HS chains binding affinities and selectivity. The large HS structural diversity results from a tightly controlled biosynthetic pathway that is differently regulated in different organs, stages of development and pathologies, including cancer. This review addresses the regulatory mechanisms underlying HS biosynthesis, with a particular focus on the catalytic activity of the enzymes responsible for HS glycan sequences and sulfation motifs, namely D-Glucuronyl C5-Epimerase, N- and O-Sulfotransferases. Moreover, we provide insights on the impact of different HS structural epitopes over HSPG-protein interactions and cell signalling, as well as on the effects of deregulated expression of HS modifying enzymes in the development and progression of cancer. Finally, we discuss the clinical potential of HS biosynthetic enzymes as novel targets for therapy, and highlight the importance of developing new HS-based tools for better patients' stratification and cancer treatment.
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Affiliation(s)
- Catarina Marques
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.,Programa Doutoral em Biologia Molecular e Celular (MCbiology), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Celso A Reis
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.,Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
| | | | - Ana Magalhães
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
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5
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Ortiz Zacarías NV, Bemelmans MP, Handel TM, de Visser KE, Heitman LH. Anticancer opportunities at every stage of chemokine function. Trends Pharmacol Sci 2021; 42:912-928. [PMID: 34521537 DOI: 10.1016/j.tips.2021.08.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 02/01/2023]
Abstract
The chemokine system, comprising 48 chemokines and 23 receptors, is critically involved in several hallmarks of cancer. Yet, despite extensive efforts from the pharmaceutical sector, only two drugs aimed at this system are currently approved for clinical use against cancer. To date, numerous pharmacological approaches have been developed to successfully intervene at different stages of chemokine function: (i) chemokine availability; (ii) chemokine-glycosaminoglycan binding; and (iii) chemokine receptor binding. Many of these strategies have been tested in preclinical cancer models, and some have advanced to clinical trials as potential anticancer therapies. Here we will review the strategies and growing pharmacological toolbox for manipulating the chemokine system in cancer, and address novel methods poised for future (pre)clinical testing.
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Affiliation(s)
- Natalia V Ortiz Zacarías
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Oncode Institute, Leiden University, Leiden, The Netherlands
| | - Martijn P Bemelmans
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Tracy M Handel
- University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA
| | - Karin E de Visser
- Oncode Institute, Leiden University, Leiden, The Netherlands; Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Laura H Heitman
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Oncode Institute, Leiden University, Leiden, The Netherlands.
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6
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Huang R, Guo L, Gao M, Li J, Xiang S. Research Trends and Regulation of CCL5 in Prostate Cancer. Onco Targets Ther 2021; 14:1417-1427. [PMID: 33664576 PMCID: PMC7921632 DOI: 10.2147/ott.s279189] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 01/20/2021] [Indexed: 12/11/2022] Open
Abstract
Prostate cancer (PCa) is considered as the most common cancer of urologic neoplasms, and its development and prognosis are associated with many factors. Chemokine receptor signaling combine with advances in advanced clinicopathological characteristics have provided new insights into the molecular landscape of prostate cancer. Chemokine (C-C motif) ligand 5 (CCL5) is an important member of the CC subfamily of chemokines. The expression of chemokine CCL5 is positively correlated with poor prognostic features in patients with PCa. Current study suggested that CCL5/CCR5 axis plays a significant role in the proliferation, metastasis, angiogenesis, drug resistance of prostate cancer cells and promotes self-renewal of prostate cancer stem cells (PCSCs). Due to the major domination in CCL5 by prostate cancer and the high cancer-specific mortality with prostate cancer, research on the CCL5/CCR5 axis effective antagonists is widespread application. However, challenges for precision oncology of CCL5/CCR5 axis and effective antagonists in CRPC remain. Herein, we summarized the crucial role of CCL5 in promoting the development of PCa and discussed the antitumor application of the antagonists of CCL5/CCR5 axis.
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Affiliation(s)
- Renlun Huang
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Lang Guo
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Menghan Gao
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Jing Li
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Songtao Xiang
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
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7
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Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment. Int J Mol Sci 2020; 21:ijms21186588. [PMID: 32916872 PMCID: PMC7554799 DOI: 10.3390/ijms21186588] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression.
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8
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Singh SK, Mishra MK, Rivers BM, Gordetsky JB, Bae S, Singh R. Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:E883. [PMID: 32260550 PMCID: PMC7226629 DOI: 10.3390/cancers12040883] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 02/06/2023] Open
Abstract
Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p < 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.
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Affiliation(s)
- Santosh K. Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Manoj K. Mishra
- Department of Biological Sciences, Alabama State University, Montgomery, AL 36101, USA;
| | - Brian M. Rivers
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Jennifer B. Gordetsky
- Departments of Pathology and Urology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Sejong Bae
- Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35205, USA;
| | - Rajesh Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA;
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10
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Jiao X, Nawab O, Patel T, Kossenkov AV, Halama N, Jaeger D, Pestell RG. Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology. Cancer Res 2019; 79:4801-4807. [PMID: 31292161 PMCID: PMC6810651 DOI: 10.1158/0008-5472.can-19-1167] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/20/2019] [Accepted: 06/27/2019] [Indexed: 12/31/2022]
Abstract
Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and "stemness". Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.
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Affiliation(s)
- Xuanmao Jiao
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, Pennsylvania
| | - Omar Nawab
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, Pennsylvania
- Xavier University School of Medicine, Woodbury, New York
| | - Tejal Patel
- Xavier University School of Medicine, Woodbury, New York
| | | | - Niels Halama
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany
| | - Dirk Jaeger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumor-Immunity, Heidelberg, Germany
| | - Richard G Pestell
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, Pennsylvania.
- Wistar Institute, Philadelphia, Pennsylvania
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Nie Y, Huang H, Guo M, Chen J, Wu W, Li W, Xu X, Lin X, Fu W, Yao Y, Zheng F, Luo ML, Saw PE, Yao H, Song E, Hu H. Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy. Clin Cancer Res 2019; 25:3873-3886. [PMID: 30890553 DOI: 10.1158/1078-0432.ccr-18-3421] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/26/2019] [Accepted: 03/12/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Yan Nie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Hongyan Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Mingyan Guo
- Department of Anesthesiology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Jiewen Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Wei Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Wende Li
- Guangdong Laboratory Animal Monitoring Institute, Guangdong Key Laboratory of Laboratory Animal, Guangzhou, Guangdong, People's Republic of China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Xiaorong Lin
- Department of Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Wenkui Fu
- Department of Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Yandan Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Fang Zheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Man-Li Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Department of Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
- Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
| | - Hai Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
- Department of Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China
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12
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Lanzi C, Cassinelli G. Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity. Molecules 2018; 23:E2915. [PMID: 30413079 PMCID: PMC6278363 DOI: 10.3390/molecules23112915] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 11/06/2018] [Accepted: 11/06/2018] [Indexed: 12/21/2022] Open
Abstract
Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential.
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Affiliation(s)
- Cinzia Lanzi
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Giuliana Cassinelli
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
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Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer. Int J Mol Sci 2018; 19:ijms19051477. [PMID: 29772686 PMCID: PMC5983686 DOI: 10.3390/ijms19051477] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 12/14/2022] Open
Abstract
Despite the progress made in molecular and clinical research, patients with advanced-stage gastric cancer (GC) have a bad prognosis and very low survival rates. Furthermore, it is challenging to find the complex molecular mechanisms that are involved in the development of GC, its progression, and its resistance to therapy. The interactions of chemokines, also known as chemotactic cytokines, with their receptors regulate immune and inflammatory responses. However, updated research demonstrates that cancer cells subvert the normal chemokine role, transforming them into fundamental constituents of the tumor microenvironment (TME) with tumor-promoting effects. C-C chemokine ligand 5 (CCL5) is a chemotactic cytokine, and its expression and secretion are regulated in T cells. C-C chemokine receptor type 5 (CCR5) is expressed in T cells, macrophages, other leukocytes, and certain types of cancer cells. The interaction between CCL5 and CCR5 plays an active role in recruiting leukocytes into target sites. This review summarizes recent information on the role of the CCL5 chemokine and its receptor CCR5 in GC cell proliferation, metastasis formation, and in the building of an immunosuppressive TME. Moreover, it highlights the development of new therapeutic strategies to inhibit the CCL5/CCR5 axis in different ways and their possible clinical relevance in the treatment of GC.
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Jacquet-Guibon S, Dupays AG, Coudry V, Crevier-Denoix N, Leroy S, Siñeriz F, Chiappini F, Barritault D, Denoix JM. Randomized controlled trial demonstrates the benefit of RGTA® based matrix therapy to treat tendinopathies in racing horses. PLoS One 2018. [PMID: 29522564 PMCID: PMC5844532 DOI: 10.1371/journal.pone.0191796] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
A randomized controlled trial was performed on racing horses, to evaluate the efficacy of a new class of therapeutic agents in regenerative medicine—ReGeneraTing Agents® (RGTA®), to treat tendinopathies. Preliminary uncontrolled studies on tendon healing in racing horses with RGTA® (OTR4131)—Equitend® showed encouraging results, justifying performing a randomized, controlled, multicenter study with a two-year racing performance follow up. The objective of this study was to evaluate the effect of Equitend® versus placebo on acute superficial digital flexor tendonitis in racing French Standardbred Trotters (ST). Twenty-two ST were randomly and blindly assigned to receive with a ratio of 2 to 1, a single Equitend® (n = 14) or placebo (n = 8) intralesional injection under ultrasonographic guidance. Horses were evaluated over 4 months, by clinical and ultrasonographic evaluations (day 0, months 1, 2, 4), and their racing performances followed up over the 2 years after treatment. During the first month of treatment, a significant decrease in the cross-sectional area (CSA) was found in the Equitend® group (p = 0.04). After 4 months, the number of Equitend® treated horses with an improved CSA was significantly higher than the placebo-treated horses (p = 0.03571). The Equitend® group returned to their pre-injury performance level, racing in, and winning, significantly more races than the placebo group (p = 0.01399 and 0.0421, respectively). Furthermore, recurrence was significantly higher in the placebo group than in the Equitend® group (71.4% vs 16.6%, p = 0.02442). In conclusion, we measured a significant, short-term, reduction effect on CSA and demonstrated a long-term beneficial effect of intralesional injection of Equitend® for the treatment of superficial digital flexor tendonitis on racing ST, racing 2. 3 times more often than placebo, with 3.3 times fewer recurrences maintaining pre-injury performance level. This study may open the way for the development of a human treatment of tendonitis.
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Affiliation(s)
- Sandrine Jacquet-Guibon
- Centre d’Imagerie et de Recherche sur les Affections Locomotrices Equines, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
- Unité Sous Contrat 957, Biomécanique et Pathologie Locomotrice du Cheval, Institut National de la Recherche Agronomique, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
- * E-mail:
| | | | - Virginie Coudry
- Centre d’Imagerie et de Recherche sur les Affections Locomotrices Equines, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
- Unité Sous Contrat 957, Biomécanique et Pathologie Locomotrice du Cheval, Institut National de la Recherche Agronomique, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
| | - Nathalie Crevier-Denoix
- Unité Sous Contrat 957, Biomécanique et Pathologie Locomotrice du Cheval, Institut National de la Recherche Agronomique, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
| | | | - Fernando Siñeriz
- Organ, Tissue, Regeneration, Repair and Replacement Société Actions Simplifiés, Paris, France
| | - Franck Chiappini
- Organ, Tissue, Regeneration, Repair and Replacement Société Actions Simplifiés, Paris, France
| | - Denis Barritault
- Organ, Tissue, Regeneration, Repair and Replacement Société Actions Simplifiés, Paris, France
- Laboratoire de recherche sur la Croissance Cellulaire, Réparation, et Régénération Tissulaire, Faculté des Sciences, Université Paris-Est Créteil, Créteil, France
| | - Jean-Marie Denoix
- Centre d’Imagerie et de Recherche sur les Affections Locomotrices Equines, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
- Unité Sous Contrat 957, Biomécanique et Pathologie Locomotrice du Cheval, Institut National de la Recherche Agronomique, Ecole Nationale vétérinaire d’Alfort, Maisons-Alfort, France
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15
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Ryu H, Baek SW, Moon JY, Jo IS, Kim N, Lee HJ. C-C motif chemokine receptors in gastric cancer. Mol Clin Oncol 2018; 8:3-8. [PMID: 29285394 PMCID: PMC5738695 DOI: 10.3892/mco.2017.1470] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 06/06/2017] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-associated mortality worldwide. Despite recent advances in molecular and clinical research, patients with gastric cancer at an advanced stage have a dismal prognosis and poor survival rates, and systemic treatment relies predominantly on traditional cytotoxic chemotherapy. To improve patients' quality of life and survival, an improved understanding of the complex molecular mechanisms involved in gastric cancer progression and treatment resistance, and of its clinical application in the development of novel targeted therapies, is urgently required. Chemokines are a group of small chemotactic cytokines that interact with seven-transmembrane G-protein-coupled receptors, and this interaction serves a crucial role in various physiological processes, including organ development and the host immune response, to recruit cells to specific sites in the body. There is also accumulating evidence that chemokines and chemokine receptors (CCRs) contribute to tumor development and progression, as well as metastasis. However, research regarding the functional roles of chemokines and their receptors in cancer is dynamic and context-dependent, and much remains to be elucidated, although various aspects have been explored extensively. In gastric cancer, C-C motif CCRs are involved in the biological behavior of tumor cells, including the processes of growth, invasion and survival, as well as the epithelial-mesenchymal transition. In the present review, attention is given to the clinical relevance of C-C motif CCRs in the development, progression, and metastasis of gastric cancer, particularly CCR7 and CCR5, which have been investigated extensively, as well as their potential therapeutic implications.
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Affiliation(s)
- Hyewon Ryu
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Seung Woo Baek
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Ji Young Moon
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - In-Sook Jo
- Department of Medical Science, School of Medicine Chungnam National University and Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Nayoung Kim
- Department of Medical Science, School of Medicine Chungnam National University and Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Hyo Jin Lee
- Department of Internal Medicine, School of Medicine Chungnam National University and Chungnam National University Hospital, Daejeon 35015, Republic of Korea
- Cancer Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea
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16
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Suffee N, Le Visage C, Hlawaty H, Aid-Launais R, Vanneaux V, Larghero J, Haddad O, Oudar O, Charnaux N, Sutton A. Pro-angiogenic effect of RANTES-loaded polysaccharide-based microparticles for a mouse ischemia therapy. Sci Rep 2017; 7:13294. [PMID: 29038476 PMCID: PMC5643514 DOI: 10.1038/s41598-017-13444-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 08/09/2017] [Indexed: 12/20/2022] Open
Abstract
Peripheral arterial disease results from the chronic obstruction of arteries leading to critical hindlimb ischemia. The aim was to develop a new therapeutic strategy of revascularization by using biodegradable and biocompatible polysaccharides-based microparticles (MP) to treat the mouse hindlimb ischemia. For this purpose, we deliver the pro-angiogenic chemokine Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES)/CCL5 in the mouse ischemic hindlimb, in solution or incorporated into polysaccharide-based microparticles. We demonstrate that RANTES-loaded microparticles improve the clinical score, induce the revascularization and the muscle regeneration in injured mice limb. To decipher the mechanisms underlying RANTES effects in vivo, we demonstrate that RANTES increases the spreading, the migration of human endothelial progenitor cells (EPC) and the formation of vascular network. The main receptors of RANTES i.e. CCR5, syndecan-4 and CD44 expressed at endothelial progenitor cell surface are involved in RANTES-induced in vitro biological effects on EPC. By using two RANTES mutants, [E66A]-RANTES with impaired ability to oligomerize, and [44AANA47]-RANTES mutated in the main RANTES-glycosaminoglycan binding site, we demonstrate that both chemokine oligomerization and binding site to glycosaminoglycans are essential for RANTES-induced angiogenesis in vitro. Herein we improved the muscle regeneration and revascularization after RANTES-loaded MP local injection in mice hindlimb ischemia.
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Affiliation(s)
- N Suffee
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - C Le Visage
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, France
| | - H Hlawaty
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - R Aid-Launais
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - V Vanneaux
- APHP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, F-75475, Paris, France.,Inserm UMR1160 et CIC de Biothérapies, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France
| | - J Larghero
- APHP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, F-75475, Paris, France.,Inserm UMR1160 et CIC de Biothérapies, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France
| | - O Haddad
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - O Oudar
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - N Charnaux
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France.,Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, Bondy, France
| | - A Sutton
- INSERM, U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France. .,Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, Bondy, France.
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17
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Marinval N, Saboural P, Haddad O, Maire M, Bassand K, Geinguenaud F, Djaker N, Ben Akrout K, Lamy de la Chapelle M, Robert R, Oudar O, Guyot E, Laguillier-Morizot C, Sutton A, Chauvierre C, Chaubet F, Charnaux N, Hlawaty H. Identification of a Pro-Angiogenic Potential and Cellular Uptake Mechanism of a LMW Highly Sulfated Fraction of Fucoidan from Ascophyllum nodosum. Mar Drugs 2016; 14:E185. [PMID: 27763505 PMCID: PMC5082333 DOI: 10.3390/md14100185] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 09/28/2016] [Accepted: 10/10/2016] [Indexed: 02/04/2023] Open
Abstract
Herein we investigate the structure/function relationships of fucoidans from Ascophyllum nodosum to analyze their pro-angiogenic effect and cellular uptake in native and glycosaminoglycan-free (GAG-free) human endothelial cells (HUVECs). Fucoidans are marine sulfated polysaccharides, which act as glycosaminoglycans mimetics. We hypothesized that the size and sulfation rate of fucoidans influence their ability to induce pro-angiogenic processes independently of GAGs. We collected two fractions of fucoidans, Low and Medium Molecular Weight Fucoidan (LMWF and MMWF, respectively) by size exclusion chromatography and characterized their composition (sulfate, fucose and uronic acid) by colorimetric measurement and Raman and FT-IR spectroscopy. The high affinities of fractionated fucoidans to heparin binding proteins were confirmed by Surface Plasmon Resonance. We evidenced that LMWF has a higher pro-angiogenic (2D-angiogenesis on Matrigel) and pro-migratory (Boyden chamber) potential on HUVECs, compared to MMWF. Interestingly, in a GAG-free HUVECs model, LMWF kept a pro-angiogenic potential. Finally, to evaluate the association of LMWF-induced biological effects and its cellular uptake, we analyzed by confocal microscopy the GAGs involvement in the internalization of a fluorescent LMWF. The fluorescent LMWF was mainly internalized through HUVEC clathrin-dependent endocytosis in which GAGs were partially involved. In conclusion, a better characterization of the relationships between the fucoidan structure and its pro-angiogenic potential in GAG-free endothelial cells was required to identify an adapted fucoidan to enhance vascular repair in ischemia.
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Affiliation(s)
- Nicolas Marinval
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Pierre Saboural
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Oualid Haddad
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Murielle Maire
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Kevin Bassand
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Frederic Geinguenaud
- Laboratoire CSPBAT, CNRS UMR 7244, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny F-93017, France.
| | - Nadia Djaker
- Laboratoire CSPBAT, CNRS UMR 7244, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny F-93017, France.
| | - Khadija Ben Akrout
- Laboratoire CSPBAT, CNRS UMR 7244, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny F-93017, France.
| | - Marc Lamy de la Chapelle
- Laboratoire CSPBAT, CNRS UMR 7244, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny F-93017, France.
| | - Romain Robert
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Olivier Oudar
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Erwan Guyot
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
- Laboratoire de Biochimie, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, Bondy 93140, France.
| | - Christelle Laguillier-Morizot
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
- Laboratoire de Biochimie, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, Bondy 93140, France.
| | - Angela Sutton
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
- Laboratoire de Biochimie, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, Bondy 93140, France.
| | - Cedric Chauvierre
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Frederic Chaubet
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
| | - Nathalie Charnaux
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
- Laboratoire de Biochimie, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, Bondy 93140, France.
| | - Hanna Hlawaty
- Inserm U1148, LVTS, Université Paris 13, Sorbonne Paris Cité, Paris 75018, France.
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18
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CXCL3 contributes to CD133(+) CSCs maintenance and forms a positive feedback regulation loop with CD133 in HCC via Erk1/2 phosphorylation. Sci Rep 2016; 6:27426. [PMID: 27255419 PMCID: PMC4891684 DOI: 10.1038/srep27426] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/09/2016] [Indexed: 12/25/2022] Open
Abstract
Although the chemotactic cytokine CXCL3 is thought to play an important role in tumor initiation and invasion, little is known about its function in hepatocellular carcinoma (HCC). In our previous study, we found that Ikaros inhibited CD133 expression via the MAPK pathway in HCC. Here, we showed that Ikaros may indirectly down-regulate CXCL3 expression in HCC cells, which leads to better outcomes in patients with CD133+ cancer stem cell (CSC) populations. CD133 overexpression induced CXCL3 expression, and silencing of CD133 down-regulated CXCL3 in HCC cells. Knockdown of CXCL3 inhibited CD133+ HCC CSCs’ self-renewal and tumorigenesis. The serum CXCL3 level was higher in HCC patients’ samples than that in healthy individual. HCC patients with higher CXCL3 expression displayed a poor prognosis, and a high level of CXCL3 was significantly associated with vascular invasion and tumor capsule formation. Exogenous CXCL3 induced Erk1/2 and ETS1 phosphorylation and promoted CD133 expression, indicating a positive feedback loop between CXCL3 and CD133 gene expression in HCC cells via Erk1/2 activation. Together, our findings indicated that CXCL3 might be a potent therapeutic target for HCC.
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19
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Baghy K, Tátrai P, Regős E, Kovalszky I. Proteoglycans in liver cancer. World J Gastroenterol 2016; 22:379-393. [PMID: 26755884 PMCID: PMC4698501 DOI: 10.3748/wjg.v22.i1.379] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 09/14/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects.
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Liang CM, Chen L, Hu H, Ma HY, Gao LL, Qin J, Zhong CP. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015; 7:1390-1402. [PMID: 26052384 PMCID: PMC4450202 DOI: 10.4254/wjh.v7.i10.1390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/08/2014] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
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21
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Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands. Structure 2015; 23:1066-77. [PMID: 25982530 DOI: 10.1016/j.str.2015.03.024] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 03/23/2015] [Accepted: 03/31/2015] [Indexed: 12/22/2022]
Abstract
Interactions of the chemokine CCL5 (RANTES) with glycosaminoglycans (GAGs) are crucial to the CCL5-mediated inflammation process. However, structural information on interactions between CCL5 and longer GAG fragments is lacking. In this study, the interactions between oligosaccharides derived from chondroitin sulfate and a dimeric variant of CCL5 were investigated using solution nuclear magnetic resonance. The data indicate that, in addition to the BBXB motif in the 40s loop, GAGs also contact residues in the N loop in a manner similar to interactions between chemokine and the receptor N terminus, leading to possible stabilization of the dimer. Using 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-tagged hexasaccharides, the binding orientation of the hexasaccharides was shown to be highly dependent on the sulfation pattern of the N-acetyl galactosamine groups. Finally, a model of the CCL5 dimer complexed to chondroitin sulfate hexasaccharides was constructed using paramagnetic relaxation enhancement and intra- and intermolecular nuclear Overhauser effect constraints.
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22
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Maillard L, Saito N, Hlawaty H, Friand V, Suffee N, Chmilewsky F, Haddad O, Laguillier C, Guyot E, Ueyama T, Oudar O, Sutton A, Charnaux N. RANTES/CCL5 mediated-biological effects depend on the syndecan-4/PKCα signaling pathway. Biol Open 2014; 3:995-1004. [PMID: 25260916 PMCID: PMC4197448 DOI: 10.1242/bio.20148227] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The perpetuation of angiogenesis is involved in certain chronic inflammatory diseases. The accelerated neovascularisation may result from an inflammatory status with a response of both endothelial cells and monocytes to inflammatory mediators such as chemokines. We have previously described in vitro and in vivo the pro-angiogenic effects of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)/CCL5. The effects of RANTES/CCL5 may be related to its binding to G protein-coupled receptors and to proteoglycans such as syndecan-1 and -4. The aim of this study was to evaluate the functionality of syndecan-4 as a co-receptor of RANTES/CCL5 by the use of mutated syndecan-4 constructs. Our data demonstrate that site-directed mutations in syndecan-4 modify RANTES/CCL5 biological activities in endothelial cells. The SDC4S179A mutant, associated with an induced protein kinase C (PKC)α activation, leads to higher RANTES/CCL5 pro-angiogenic effects, whereas the SDC4L188QQ and the SDC4A198del mutants, leading to lower phosphatidylinositol 4,5-bisphosphate (PIP2) binding or to lower PDZ protein binding respectively, are associated with reduced RANTES/CCL5 cellular effects. Moreover, our data highlight that the intracellular domain of SDC-4 is involved in RANTES/CCL5-induced activation of the PKCα signaling pathway and biological effect. As RANTES/CCL5 is involved in various physiopathological processes, the development of a new therapeutic strategy may be reliant on the mechanism by which RANTES/CCL5 exerts its biological activities, for example by targeting the binding of the chemokine to its proteoglycan receptor.
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Affiliation(s)
- Loïc Maillard
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Naoaki Saito
- Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan
| | - Hanna Hlawaty
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Véronique Friand
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Nadine Suffee
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Fanny Chmilewsky
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Oualid Haddad
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Christelle Laguillier
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France
| | - Erwan Guyot
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France
| | - Takehiko Ueyama
- Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan
| | - Olivier Oudar
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France
| | - Angela Sutton
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France
| | - Nathalie Charnaux
- Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France
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Bai H, Weng Y, Bai S, Jiang Y, Li B, He F, Zhang R, Yan S, Deng F, Wang J, Shi Q. CCL5 secreted from bone marrow stromal cells stimulates the migration and invasion of Huh7 hepatocellular carcinoma cells via the PI3K-Akt pathway. Int J Oncol 2014; 45:333-43. [PMID: 24806733 DOI: 10.3892/ijo.2014.2421] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Accepted: 04/14/2014] [Indexed: 11/06/2022] Open
Abstract
Bone metastases from hepatocellular carcinoma (HCC) seem to be increasing. Previous studies showed that soluble factors secreted by host cells and direct cell-to-cell interactions contributed to the preferential metastasis and growth of cancer cells in bone, while the underlying mechanism(s) of the metastasis of HCC in the bone are poorly understood. Here, we determined the effect of HS-5 cells on Huh7 cell proliferation, and investigated the role of CCL5 from HS-5 cells on the development of Huh7 cells. In addition, the underlying mechanisms on the influence in Huh7 cells were investigated. Our results showed that HS-5 cells could promote the proliferation, migration and invasion of Huh7 cells, and inhibited apoptosis. CCL5 downregulation was able to inhibit the effects of HS-5 cells on Huh7 cell migration and invasion via the PI3K-Akt signaling pathway and reduce MMP-2 expression. Therefore, these findings suggest that CCL5 secreted from MSCs can promote the migration and invasion of Huh7 cells and could be an important factor in HCC related to occurrence of bone metastases.
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Affiliation(s)
- Huili Bai
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yaguang Weng
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shunjie Bai
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yingjiu Jiang
- The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Baolin Li
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Fang He
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ruyi Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shujuan Yan
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Fang Deng
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jing Wang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Qiong Shi
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
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The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett 2013; 352:36-53. [PMID: 24141062 DOI: 10.1016/j.canlet.2013.10.006] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 10/07/2013] [Accepted: 10/10/2013] [Indexed: 11/21/2022]
Abstract
Chemokines and their receptors regulate the trafficking of leukocytes in hematopoiesis and inflammation, and thus are fundamental to the immune integrity of the host. In parallel, members of the chemokine system exert a large variety of functions that dictate processes of cancer development and progression. Chemokines can act as pro-tumoral or anti-tumoral regulators of malignancy by affecting cells of the tumor microenvironment (leukocytes, endothelial cells, fibroblasts) and the tumor cells themselves (migration, invasion, proliferation, resistance to chemotherapy). Several of the chemokines are generally skewed towards the cancer-promoting direction, including primarily the CCR5-CCL5 (RANTES) and the CXCR4-CXCL12 (SDF-1) axes. This review provides a general view of chemokines and chemokine receptors as regulators of malignancy, describing their multi-faceted activities in cancer. The tumor-promoting activities of the CCR5-CCL5 and CXCR4-CXCL12 pathways are enlightened, emphasizing their potential use as targets for personalized therapy. Indeed, novel blockers of chemokines and their receptors are constantly emerging, and two chemokine receptor inhibitors were recently approved for clinical use: Maraviroc for CCR5 and Plerixafor for CXCR4. The review addresses ongoing pre-clinical and clinical trials using these modalities and others in cancer. Then, challenges and opportunities of personalized therapy directed against chemokines and their receptors in malignancy are discussed, demonstrating that such novel personalized cancer therapies hold many challenges, but also offer hope for cancer patients.
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25
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Guerriero E, Capone F, Rusolo F, Colonna G, Castello G, Costantini S. Dissimilar cytokine patterns in different human liver and colon cancer cell lines. Cytokine 2013; 64:584-9. [PMID: 24064000 DOI: 10.1016/j.cyto.2013.09.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 08/20/2013] [Accepted: 09/01/2013] [Indexed: 12/14/2022]
Abstract
An accurate and simultaneous estimate of cellular levels of a large cytokine number is very useful to obtain information about an organ dysfunction leading to cancer because through the understanding of the evolution of cytokine patterns we can recognize and predict the disease progression. Cancer cell lines are commonly used to study the cancer microenvironment, to analyze their chemosensitivity and carcinogenesis as well as to test in vitro the effect of molecules, such as drugs or anti-oxidants, on the inflammation status and its progression. We noted that various cell lines commonly used as a model for studies on liver and colon cancer possess different patterns of cytokines. This aspect may generate data not comparable in laboratories using different cell lines; thus, to investigate the origin of these abnormalities we compared the cell lines HepG2 and Huh7, and HT-29 and HCT-116, for liver and colon cancer, respectively. In this context we have evaluated and compared the levels of cytokines, chemokines and growth factors in the supernatants of these cellular lines. Our aim was to identify what cytokines were significantly different correlating similarities and differences to the specific inflammation status of each cellular model of cancer.
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Affiliation(s)
- Eliana Guerriero
- Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Italy
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Severin IC, Soares A, Hantson J, Teixeira M, Sachs D, Valognes D, Scheer A, Schwarz MK, Wells TNC, Proudfoot AEI, Shaw J. Glycosaminoglycan analogs as a novel anti-inflammatory strategy. Front Immunol 2012; 3:293. [PMID: 23087686 PMCID: PMC3472544 DOI: 10.3389/fimmu.2012.00293] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 09/03/2012] [Indexed: 01/07/2023] Open
Abstract
Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti-inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.
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Affiliation(s)
| | | | | | - Mauro Teixeira
- Departmento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas GeraisBelo Horizonte, Brazil
| | - Daniela Sachs
- Departmento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas GeraisBelo Horizonte, Brazil
| | | | | | | | | | - Amanda E. I. Proudfoot
- Merck Serono Geneva Research CentreGeneva, Switzerland,*Correspondence: Amanda E. I. Proudfoot and Jeffrey Shaw, Merck Serono Geneva Research Centre, 9, Chemin des Mines, 1202 Geneva, Switzerland. e-mail: ;
| | - Jeffrey Shaw
- Merck Serono Geneva Research CentreGeneva, Switzerland,*Correspondence: Amanda E. I. Proudfoot and Jeffrey Shaw, Merck Serono Geneva Research Centre, 9, Chemin des Mines, 1202 Geneva, Switzerland. e-mail: ;
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Tsai HT, Yang SF, Chen DR, Chan SE. CCL5-28, CCL5-403, and CCR5 genetic polymorphisms and their synergic effect with alcohol and tobacco consumptions increase susceptibility to hepatocellular carcinoma. Med Oncol 2012; 29:2771-9. [PMID: 22374185 DOI: 10.1007/s12032-012-0189-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 02/06/2012] [Indexed: 12/20/2022]
Abstract
The aim of this study was to estimate the relationship between gene polymorphisms of CCL5-28, CCL5-403, and CCR5 to the susceptibility of hepatocellular carcinoma (HCC). A total of 449 subjects, including 347 healthy controls and 102 patients with HCC, were recruited in this study and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to investigate the impact of these two polymorphic variants on HCC. A significant association between HCC susceptibility and genetic polymorphism, CG heterozygotes of CCL5-28 (AOR=2.35; 95% CI=1.27-4.33, p=0.006), AA homozygotes of CCL5-403 (AOR=5.18; 95% CI=2.25-11.91, p=0.0001), and AA homozygotes of CCR5 (AOR=2.47; 95% CI=1.24-4.90, p=0.009), was found compared with wild genotype after adjusting for other confounders. It was detected that synergistic effect between gene-to-gene polymorphisms increased the risk to have HCC among individuals with CG or GG of CCL5-28, and GA or AA of CCL-403, and GA or AA of CCR5 (AOR=3.42; 95% CI=1.39-8.38, p=0.007) compared to individuals with wild genotypes of CCL5-28, CCL-403, and CCR5. Also, alcohol or tobacco consumption increased the risk to have HCC among subjects with CG heterozygotes of CCL5-28 (alcohol: p=0.001; tobacco: p=0.006), AA homozygotes (alcohol: p=0.0004; tobacco: p≤0.0001) or GA heterozygotes (tobacco: p=0.03) of CCL5-403, and AA homozygotes of CCR5 (alcohol: p=0.02; tobacco: p=0.02), respectively. Gene polymorphisms of CCL5-28, CCL5-403, and CCR5 play an important factor for the susceptibility of HCC, respectively. The synergic effects of these two gene polymorphisms to tobacco or alcohol consumption significantly increase the risk to develop HCC.
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Affiliation(s)
- Hsiu-Ting Tsai
- School of Nursing, Chung Shan Medical University, 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan, ROC.
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Selective targeting of genetically engineered mesenchymal stem cells to tumor stroma microenvironments using tissue-specific suicide gene expression suppresses growth of hepatocellular carcinoma. Ann Surg 2012; 254:767-74; discussion 774-5. [PMID: 22042469 DOI: 10.1097/sla.0b013e3182368c4f] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The use of engineered mesenchymal stem cells (MSCs) as therapeutic vehicles for the treatment of experimental pancreatic and breast cancer has been previously demonstrated. The potential application of MSCs for the treatment of hepatocellular carcinoma (HCC) has been controversial. The general approach uses engineered MSCs to target different aspects of tumor biology, including angiogenesis or the fibroblast-like stromal compartment, through the use of tissue-specific expression of therapeutic transgenes. The aim of the present study was (1) to evaluate the effect of exogenously added MSCs on the growth of HCC and (2) the establishment of an MSC-based suicide gene therapy for experimental HCC. METHODS Mesenchymal stem cells were isolated from bone marrow of C57/Bl6 p53(-/-) mice. The cells were injected into mice with HCC xenografts and the effect on tumor proliferation and angiogenesis was evaluated. The cells were then stably transfected with red fluorescent protein (RFP) or Herpes simplex virus thymidine kinase (HSV-Tk) gene under control of the Tie2 promoter/enhancer or the CCL5 promoter. Mesenchymal stem cells were injected intravenously into mice with orthotopically growing xenografts of HCC and treated with ganciclovir (GCV). RESULTS Ex vivo examination of hepatic tumors revealed tumor-specific recruitment, enhanced tumor growth, and increased microvessel density after nontherapeutic MSC injections. After their homing to the hepatic xenografts, engineered MSCs demonstrated activation of the Tie2 or CCL5 promoter as shown by RFP expression. Application of CCL5/HSV-TK transfected MSCs in combination with GCV significantly reduced tumor growth by 56.4% as compared with the control group and by 71.6% as compared with nontherapeutic MSC injections. CCL5/HSV-TK(+) transfected MSCs proved more potent in tumor inhibition as compared with Tie2/HSV-TK(+) MSCs. CONCLUSION Exogenously added MSCs are recruited to growing HCC xenografts with concomitant activation of the CCL5 or Tie2 promoters within the MSCs. Stem cell-mediated introduction of suicide genes into the tumor followed by prodrug administration was effective for treatment of experimental HCC and thus may help fill the existing gap in bridging therapies for patients suffering from advanced HCCs.
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Abstract
Heparin and glycosaminoglycans (GAGs) related structurally to heparin, notably heparan sulphate, bind to most, if not all, chemokines and many growth factors. The chemokine and growth factor interactions with GAGs localise the peptide mediators to specific sites in tissues and influence their stability and function. This chapter discusses the nature of these interactions and the effect on the function of a number of chemokines (PF-4, interleukin-8, RANTES and SDF-1) and growth factors (FGF, HGF, VEGF) in normal physiology and the disease setting. Novel therapeutic interventions that target chemokine and growth factor interactions with GAGs are also discussed.
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Role of RANTES and its receptor in gastric cancer metastasis. ACTA ACUST UNITED AC 2011; 31:342-347. [PMID: 21671175 DOI: 10.1007/s11596-011-0378-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Indexed: 12/30/2022]
Abstract
This study examined the role of regulated upon activation normal T cell expressed and secreted (RANTES) and its receptor C-C chemokine receptor type 5 (CCR5) in gastric cancer metastasis and the associated mechanism. The expression of RANTES and CCR5 was detected by using immunohistochemical staining and Western blotting in the gastric cancer tissues obtained from 60 gastric cancer patients with or without lymph node metastasis (n=30 in each). The results showed that the expression levels of RANTES and CCR5 were higher in gastric cancer with lymph node metastasis than in that without metastasis (P<0.05). The expression levels of RANTES in 30 lymph nodes with cancerous invasion were higher than in 30 normal lymph nodes (P<0.05). Chemotactic test revealed that the number of migrating gastric cancer cells (n=295.0 ± 54.6) induced by the protein of cancer-invading lymph nodes was greater than that by the protein mixture from cancer-invading lymph nodes and RANTES antibody (n=42.5 ± 11.6) (P<0.05). RT-PCR showed that the expression levels of the main Th1 cytokines (IL-2, Γ-IFN) were lower in gastric cancer with lymph node metastasis (2.22 ± 0.90, 3.26 ± 1.15 respectively) than in that without metastasis (3.07 ± 1.67, 4.77 ± 1.52 respectively) (P<0.05), but the expression level of the main Th 2 cytokine (IL-10) was higher in gastric cancer with lymph nodes metastasis (6.06 ± 2.04) than in that without metastasis (4.88 ± 1.87) (P<0.05). It was concluded that RANTES and its receptor CCR5 may contribute to gastric cancer metastasis through influencing the balance of Th1/Th2. RANTES and CCR5 may become a marker of gastric cancer metastasis.
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Charni F, Sutton A, Rufat P, Laguillier C, Mansouri A, Moreau R, Ganne-Carrié N, Trinchet JC, Beaugrand M, Charnaux N, Nahon P. Chemokine RANTES Promoter Dimorphisms and Hepatocellular Carcinoma Occurrence in Patients with Alcoholic or Hepatitis C Virus–Related Cirrhosis. Cancer Epidemiol Biomarkers Prev 2011; 20:1439-46. [DOI: 10.1158/1055-9965.epi-11-0341] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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McLean MH, Murray GI, Stewart KN, Norrie G, Mayer C, Hold GL, Thomson J, Fyfe N, Hope M, Mowat NAG, Drew JE, El-Omar EM. The inflammatory microenvironment in colorectal neoplasia. PLoS One 2011; 6:e15366. [PMID: 21249124 PMCID: PMC3017541 DOI: 10.1371/journal.pone.0015366] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 11/11/2010] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.
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Affiliation(s)
- Mairi H McLean
- Gastrointestinal Research Group, School of Medicine and Dentistry, Aberdeen University, Aberdeen, United Kingdom
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Ikeda Y, Charef S, Ouidja MO, Barbier-Chassefière V, Sineriz F, Duchesnay A, Narasimprakash H, Martelly I, Kern P, Barritault D, Petit E, Papy-Garcia D. Synthesis and biological activities of a library of glycosaminoglycans mimetic oligosaccharides. Biomaterials 2011; 32:769-76. [DOI: 10.1016/j.biomaterials.2010.09.043] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Accepted: 09/19/2010] [Indexed: 11/26/2022]
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Abstract
Chemokines play a paramount role in tumor progression. In hepatocellular carcinoma (HCC) progression, chemokines and their receptors play an intricate role. Currently, chemokines and their receptors such as the CXCL12-CXCR4 axis, CX3CL1-CX3CR1 axis and the CCL20-CCR6 axis have received much research attention. Although a large number of studies show that these axes are strongly associated with HCC, the exact mechanism by which these axes promote the growth and progression of HCC remains unknown. In this paper, several chemokines and their receptor interactions in HCC progression, growth and metastasis and immune response to HCC are reviewed.
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Nilsson U, Johnsson R, Fransson LÅ, Ellervik U, Mani K. Attenuation of Tumor Growth by Formation of Antiproliferative Glycosaminoglycans Correlates with Low Acetylation of Histone H3. Cancer Res 2010; 70:3771-9. [DOI: 10.1158/0008-5472.can-09-4331] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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36
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Dagouassat M, Suffee N, Hlawaty H, Haddad O, Charni F, Laguillier C, Vassy R, Martin L, Schischmanoff PO, Gattegno L, Oudar O, Sutton A, Charnaux N. Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. Int J Cancer 2010; 126:1095-108. [PMID: 19642141 DOI: 10.1002/ijc.24800] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein-coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by beta-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.
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Affiliation(s)
- Maylis Dagouassat
- INSERM U698, Bioingénierie cardiovasculaire, Université Paris 13, Bobigny, France
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Albanese P, Caruelle D, Frescaline G, Delbé J, Petit-Cocault L, Huet E, Charnaux N, Uzan G, Papy-Garcia D, Courty J. Glycosaminoglycan mimetics–induced mobilization of hematopoietic progenitors and stem cells into mouse peripheral blood: Structure/function insights∗. Exp Hematol 2009; 37:1072-83. [DOI: 10.1016/j.exphem.2009.06.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2008] [Revised: 05/18/2009] [Accepted: 06/09/2009] [Indexed: 10/20/2022]
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Friand V, Haddad O, Papy-Garcia D, Hlawaty H, Vassy R, Hamma-Kourbali Y, Perret GY, Courty J, Baleux F, Oudar O, Gattegno L, Sutton A, Charnaux N. Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells. Glycobiology 2009; 19:1511-24. [PMID: 19717493 DOI: 10.1093/glycob/cwp130] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We have recently reported that the CXC-chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 induces proliferation, migration, and invasion of the Huh7 human hepatoma cells through its G-protein-coupled receptor CXCR4 and that glycosaminoglycans (GAGs) are involved in these events. Here, we demonstrate by surface plasmon resonance that the chemokine binds to GAG mimetics obtained by grafting carboxylate, sulfate or acetate groups onto a dextran backbone. We also demonstrate that chemically modified dextrans inhibit SDF-1/CXCL12-mediated in vitro chemotaxis and anchorage-independent cell growth in a dose-dependent manner. The binding of GAG mimetics to the chemokine and their effects in modulating the SDF-1/CXCL12 biological activities are mainly related to the presence of sulfate groups. Furthermore, the mRNA expression of enzymes involved in heparan sulfate biosynthesis, such as exostosin-1 and -2 or N-deacetylase N-sulfotransferases remained unchanged, but heparanase mRNA and protein expressions in Huh7 cells were decreased upon GAG mimetic treatment. Moreover, decreasing heparanase-1 mRNA levels by RNA interference significantly reduced SDF-1/CXCL12-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Therefore, we suggest that GAG mimetic effects on SDF-1/CXCL12-mediated hepatoma cell chemotaxis may rely on decreased heparanase expression, which impairs SDF-1/CXCL12's signaling. Altogether, these data suggest that GAG mimetics may compete with cellular heparan sulfate chains for the binding to SDF-1/CXCL12 and may affect heparanase expression, leading to reduced SDF-1/CXCL12 mediated in vitro chemotaxis and growth of hepatoma cells.
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Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells. Biochim Biophys Acta Gen Subj 2009; 1790:1314-26. [PMID: 19632304 DOI: 10.1016/j.bbagen.2009.07.015] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 07/12/2009] [Accepted: 07/20/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND We previously demonstrated that the CC-chemokine Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES)/CCL5 exerts pro-tumoral effects on human hepatoma Huh7 cells through its G protein-coupled receptor, CCR1. Glycosaminoglycans play major roles in these biological events. METHODS In the present study, we explored 1/ the signalling pathways underlying RANTES/CCL5-mediated hepatoma cell migration or invasion by the use of specific pharmacological inhibitors, 2/ the role of RANTES/CCL5 oligomerization in these effects by using a dimeric RANTES/CCL5, 3/ the possible involvement of two membrane heparan sulfate proteoglycans, syndecan-1 (SDC-1) and syndecan-4 (SDC-4) in RANTES/CCL5-induced cell chemotaxis and spreading by pre-incubating cells with specific antibodies or by reducing SDC-1 or -4 expression by RNA interference. RESULTS AND CONCLUSION The present data suggest that focal adhesion kinase phosphorylation, phosphoinositide 3-kinase-, mitogen-activated protein kinase- and Rho kinase activations are involved in RANTES/CCL5 pro-tumoral effects on Huh7 cells. Interference with oligomerization of the chemokine reduced RANTES/CCL5-mediated cell chemotaxis. This study also indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. These results also further demonstrate the involvement of glycosaminoglycans as the glycosaminoglycan-binding deficient RANTES/CCL5 variant, in which arginine 47 was replaced by lysine, was devoid of effect. GENERAL SIGNIFICANCE The modulation of RANTES/CCL5-mediated cellular effects by targeting the chemokine-syndecan interaction could represent a new therapeutic approach for hepatocellular carcinoma.
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Jan YJ, Ko BS, Hsu C, Chang TC, Chen SC, Wang J, Liou JY. Overexpressed focal adhesion kinase predicts a higher incidence of extrahepatic metastasis and worse survival in hepatocellular carcinoma. Hum Pathol 2009; 40:1384-90. [PMID: 19454363 DOI: 10.1016/j.humpath.2009.03.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2008] [Revised: 03/04/2009] [Accepted: 03/04/2009] [Indexed: 10/20/2022]
Abstract
Focal adhesion kinase plays a critical role in cancer progression, invasion, and metastasis. Although focal adhesion kinase overexpression indicates poor prognoses for hepatocellular carcinoma, its role in hepatocellular carcinoma metastasis has not been well investigated. In this study, 55 hepatocellular carcinoma patients were enrolled, and their primary liver tumors as well as 18 matched metastases were subjected to semiquantitative immunohistochemistry analysis of focal adhesion kinase expression. Overexpression of focal adhesion kinase was observed in 34 (61.8%) of 55 primary tumors and significantly predicted subsequent extrahepatic metastases (P = .04). Metastatic tumors expressed higher focal adhesion kinase than their matched primaries (P = .010). Focal adhesion kinase overexpression indicated both worse overall 5-year survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .004) and 5-year progression-free survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .041). Taken together, we demonstrated here that focal adhesion kinase expression is significantly related to subsequent hepatocellular carcinoma metastasis. Focal adhesion kinase is thus considered as a reasonable target for novel therapies against hepatocellular carcinoma progression and metastasis.
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Affiliation(s)
- Yee-Jee Jan
- Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; College of Medicine and Nursing, Hungkuang University, Taichung 433, Taiwan
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Abstract
A surge in interest in the chemokine–chemokine receptor network is probably related to the expanding roles that chemokines have now been identified to play in human biology, particularly immunity. Specific tissue microenvironments express distinct chemokines and both hematopoietic and nonhematopoietic cells have receptor expression profiles that permit the coordinated trafficking and organization of cells within these specific tissues. Since the chemokine network plays critical roles in both the function of the immune system and the progression of cancer, it is an attractive target for therapeutic manipulation. This review will focus on chemokine and chemokine receptor network-related therapeutic interventions that utilize host–tumor interactions particularly involving the immune system.
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Affiliation(s)
- Trina J Stewart
- Cancer Immunology Research Program, The Peter MacCallum Cancer Centre, Level 2 Smorgon Family Building, St Andrews Place, East Melbourne, Victoria, 3002, Australia
| | - Mark J Smyth
- Cancer Immunology Research Program, The Peter MacCallum Cancer Centre, Level 2 Smorgon Family Building, St Andrews Place, East Melbourne, Victoria, 3002, Australia
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Rich RL, Myszka DG. Survey of the year 2007 commercial optical biosensor literature. J Mol Recognit 2008; 21:355-400. [DOI: 10.1002/jmr.928] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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