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1
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Miller WE, O'Connor CM. CMV-encoded GPCRs in infection, disease, and pathogenesis. Adv Virus Res 2024; 118:1-75. [PMID: 38461029 DOI: 10.1016/bs.aivir.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2024]
Abstract
G protein coupled receptors (GPCRs) are seven-transmembrane domain proteins that modulate cellular processes in response to external stimuli. These receptors represent the largest family of membrane proteins, and in mammals, their signaling regulates important physiological functions, such as vision, taste, and olfaction. Many organisms, including yeast, slime molds, and viruses encode GPCRs. Cytomegaloviruses (CMVs) are large, betaherpesviruses, that encode viral GPCRs (vGPCRs). Human CMV (HCMV) encodes four vGPCRs, including UL33, UL78, US27, and US28. Each of these vGPCRs, as well as their rodent and primate orthologues, have been investigated for their contributions to viral infection and disease. Herein, we discuss how the CMV vGPCRs function during lytic and latent infection, as well as our understanding of how they impact viral pathogenesis.
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Affiliation(s)
- William E Miller
- Department of Molecular and Cellular Bioscience, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Christine M O'Connor
- Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, OH, United States; Case Comprehensive Cancer Center, Cleveland, OH, United States.
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2
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Pantalone MR, Almazan NM, Lattanzio R, Taher C, De Fabritiis S, Valentinuzzi S, Bishehsari F, Mahdavinia M, Verginelli F, Rahbar A, Mariani-Costantini R, Söderberg-Naucler C. Human cytomegalovirus infection enhances 5‑lipoxygenase and cycloxygenase‑2 expression in colorectal cancer. Int J Oncol 2023; 63:116. [PMID: 37654195 PMCID: PMC10546380 DOI: 10.3892/ijo.2023.5564] [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: 07/06/2022] [Accepted: 07/07/2023] [Indexed: 09/02/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are unknown. Human cytomegalovirus (HCMV), a virus that induces inflammation and other cancer hallmarks, has been detected in several types of malignancy, including CRC. The present study investigated whether HCMV infection was associated with expression of the pro‑inflammatory enzymes 5‑lipoxygenase (5‑LO) and cyclooxygenase‑2 (COX‑2) and other molecular, genetic and clinicopathological CRC features. The present study assessed 146 individual paraffin‑embedded CRC tissue microarray (TMA) cores already characterized for TP53 and KRAS mutations, microsatellite instability (MSI) status, Ki‑67 index and EGFR by immunohistochemistry (IHC). The cores were further analyzed by IHC for the expression of two HCMV proteins (Immediate Early, IE and pp65) and the inflammatory markers 5‑LO and COX‑2. The CRC cell lines Caco‑2 and LS‑174T were infected with HCMV strain VR1814, treated with antiviral drug ganciclovir (GCV) and/or anti‑inflammatory drug celecoxib (CCX) and analyzed by reverse transcription‑quantitative PCR and immunofluorescence for 5‑LO, COX‑2, IE and pp65 transcripts and proteins. HCMV IE and pp65 proteins were detected in ~90% of the CRC cases tested; this was correlated with COX‑2, 5‑LO and KI‑67 expression, but not with EGFR immunostaining, TP53 and KRAS mutations or MSI status. In vitro, HCMV infection upregulated 5‑LO and COX‑2 transcript and proteins in both Caco‑2 and LS‑174T cells and enhanced cell proliferation as determined by MTT assay. Treatment with GCV and CCX significantly decreased the transcript levels of COX‑2, 5‑LO, HCMV IE and pp65 in infected cells. HCMV was widely expressed in CRC and may promote inflammation and serve as a potential new target for CRC therapy.
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Affiliation(s)
- Mattia Russel Pantalone
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, 17164 Stockholm, Sweden
- Center for Advanced Studies and Technology, G. d'Annunzio University, I-66100 Chieti, Italy
| | - Nerea Martin Almazan
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden
- Department of Laboratory Medicine, Unit of Microbial Pathogenesis, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Rossano Lattanzio
- Center for Advanced Studies and Technology, G. d'Annunzio University, I-66100 Chieti, Italy
- Department of Innovative Technologies in Medicine & Dentistry, G. d'Annunzio University, I-66100 Chieti, Italy
| | - Chato Taher
- Department of Basic Sciences, Hawler Medical University, Erbil 44001, Iraq
| | - Simone De Fabritiis
- Center for Advanced Studies and Technology, G. d'Annunzio University, I-66100 Chieti, Italy
- Department of Innovative Technologies in Medicine & Dentistry, G. d'Annunzio University, I-66100 Chieti, Italy
| | - Silvia Valentinuzzi
- Center for Advanced Studies and Technology, G. d'Annunzio University, I-66100 Chieti, Italy
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, I-66100 Chieti, Italy
| | - Faraz Bishehsari
- Division of Digestive Diseases, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL 60612, USA
- Digestive Disease Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 14114, Iran
| | - Mahboobeh Mahdavinia
- Digestive Disease Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 14114, Iran
- Department of Internal Medicine, Division of Allergy and Immunology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Fabio Verginelli
- Center for Advanced Studies and Technology, G. d'Annunzio University, I-66100 Chieti, Italy
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, I-66100 Chieti, Italy
| | - Afsar Rahbar
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, 17164 Stockholm, Sweden
| | | | - Cecilia Söderberg-Naucler
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, 17164 Stockholm, Sweden
- MediCity Research Laboratory, University of Turku, FI-20014 Turku, Finland
- Institute of Biomedicine, University of Turku, FI-20014 Turku, Finland
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3
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Dirck A, Diggins NL, Crawford LB, Perez WD, Parkins CJ, Struthers HH, Turner R, Pham AH, Mitchell J, Papen CR, Malouli D, Hancock MH, Caposio P. HCMV UL8 interaction with β-catenin and DVL2 regulates viral reactivation in CD34 + hematopoietic progenitor cells. J Virol 2023; 97:e0124123. [PMID: 37772824 PMCID: PMC10617580 DOI: 10.1128/jvi.01241-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 08/15/2023] [Indexed: 09/30/2023] Open
Abstract
IMPORTANCE CD34+ hematopoietic progenitor cells (HPCs) are an important cellular reservoir for latent human cytomegalovirus (HCMV). Several HCMV genes are expressed during latency that are involved with the maintenance of the viral genome in CD34+ HPC. However, little is known about the process of viral reactivation in these cells. Here, we describe a viral protein, pUL8, and its interaction and stabilization with members of the Wnt/β-catenin pathway as an important component of viral reactivation. We further define that pUL8 and β-catenin interact with DVL2 via a PDZ-binding domain, and loss of UL8 interaction with β-catenin-DVL2 restricts viral reactivation. Our findings will be instrumental in understanding the molecular processes involved in HCMV reactivation in order to design new antiviral therapeutics.
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Affiliation(s)
- Aaron Dirck
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Nicole L. Diggins
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Lindsey B. Crawford
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Wilma D. Perez
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Christopher J. Parkins
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Hillary H. Struthers
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Rebekah Turner
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Andrew H. Pham
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Jennifer Mitchell
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Courtney R. Papen
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Daniel Malouli
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Meaghan H. Hancock
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Patrizia Caposio
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA
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4
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Bergkamp ND, van Senten JR, Brink HJ, Bebelman MP, van den Bor J, Çobanoğlu TS, Dinkla K, Köster J, Klau G, Siderius M, Smit MJ. A virally encoded GPCR drives glioblastoma through feed-forward activation of the SK1-S1P 1 signaling axis. Sci Signal 2023; 16:eade6737. [PMID: 37582160 DOI: 10.1126/scisignal.ade6737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 07/27/2023] [Indexed: 08/17/2023]
Abstract
The G protein-coupled receptor (GPCR) US28 encoded by the human cytomegalovirus (HCMV) is associated with accelerated progression of glioblastomas, aggressive brain tumors with a generally poor prognosis. Here, we showed that US28 increased the malignancy of U251 glioblastoma cells by enhancing signaling mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that stimulates oncogenic pathways in glioblastoma. US28 expression increased the abundance of the key components of the S1P signaling axis, including an enzyme that generates S1P [sphingosine kinase 1 (SK1)], an S1P receptor [S1P receptor 1 (S1P1)], and S1P itself. Enhanced S1P signaling promoted glioblastoma cell proliferation and survival by activating the kinases AKT and CHK1 and the transcriptional regulators cMYC and STAT3 and by increasing the abundance of cancerous inhibitor of PP2A (CIP2A), driving several feed-forward signaling loops. Inhibition of S1P signaling abrogated the proliferative and anti-apoptotic effects of US28. US28 also activated the S1P signaling axis in HCMV-infected cells. This study uncovers central roles for S1P and CIP2A in feed-forward signaling that contributes to the US28-mediated exacerbation of glioblastoma.
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Affiliation(s)
- Nick D Bergkamp
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jeffrey R van Senten
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Hendrik J Brink
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Maarten P Bebelman
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jelle van den Bor
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Tuğçe S Çobanoğlu
- Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | | | - Johannes Köster
- Algorithms for Reproducible Bioinformatics, Institute of Human Genetics, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Medical Oncology, Harvard Medical School, Harvard University, Boston, MA, USA
| | - Gunnar Klau
- Algorithmic Bioinformatics, Department of Computer Science, Heinrich Heine University, Düsseldorf, Germany
| | - Marco Siderius
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Martine J Smit
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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5
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Yu C, He S, Zhu W, Ru P, Ge X, Govindasamy K. Human cytomegalovirus in cancer: the mechanism of HCMV-induced carcinogenesis and its therapeutic potential. Front Cell Infect Microbiol 2023; 13:1202138. [PMID: 37424781 PMCID: PMC10327488 DOI: 10.3389/fcimb.2023.1202138] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/08/2023] [Indexed: 07/11/2023] Open
Abstract
Cancer is one of the leading causes of death worldwide. Human cytomegalovirus (HCMV), a well-studied herpesvirus, has been implicated in malignancies derived from breast, colorectal muscle, brain, and other cancers. Intricate host-virus interactions are responsible for the cascade of events that have the potential to result in the transformed phenotype of normal cells. The HCMV genome contains oncogenes that may initiate these types of cancers, and although the primary HCMV infection is usually asymptomatic, the virus remains in the body in a latent or persistent form. Viral reactivation causes severe health issues in immune-compromised individuals, including cancer patients, organ transplants, and AIDS patients. This review focuses on the immunologic mechanisms and molecular mechanisms of HCMV-induced carcinogenesis, methods of HCMV treatment, and other studies. Studies show that HCMV DNA and virus-specific antibodies are present in many types of cancers, implicating HCMV as an important player in cancer progression. Importantly, many clinical trials have been initiated to exploit HCMV as a therapeutic target for the treatment of cancer, particularly in immunotherapy strategies in the treatment of breast cancer and glioblastoma patients. Taken together, these findings support a link between HCMV infections and cellular growth that develops into cancer. More importantly, HCMV is the leading cause of birth defects in newborns, and infection with HCMV is responsible for abortions in pregnant women.
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Affiliation(s)
- Chuan Yu
- Animal Diseases and Public Health Engineering Research Center of Henan Province, Luoyang Polytechnic, Luoyang, Henan, China
| | - Suna He
- Department of Pharmaceutical Sciences, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, Henan, China
| | - Wenwen Zhu
- Animal Diseases and Public Health Engineering Research Center of Henan Province, Luoyang Polytechnic, Luoyang, Henan, China
| | - Penghui Ru
- Animal Diseases and Public Health Engineering Research Center of Henan Province, Luoyang Polytechnic, Luoyang, Henan, China
| | - Xuemei Ge
- School of Light Industry and Food Engineering, Nanjing Forestry University, Nanjing, Jiangsu, China
| | - Kavitha Govindasamy
- School of Arts and Science, Rutgers, the State University of New Jersey, Newark, NJ, United States
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6
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Asano T, Suzuki H, Tanaka T, Kaneko MK, Kato Y. Identification of the Binding Epitope of an Anti-mouse CCR4 Monoclonal Antibody, C 4Mab-1. Monoclon Antib Immunodiagn Immunother 2022; 41:214-220. [PMID: 35917564 DOI: 10.1089/mab.2022.0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
C-C chemokine receptor 4 (CCR4) is one of G protein-coupled receptors, and interacts with chemokines, CCL17 and CCL22. CCR4 is expressed on T cells such as helper T type 2 cells, regulatory T cells, and interleukin 17-producing T helper cells. CCR4 is associated with T cells trafficking into the tumor microenvironment, and is associated with tumor progression or metastasis. Therefore, CCR4 may be a potential therapeutic option for T cell malignancies. C4Mab-1 is a novel anti-mouse CCR4 (mCCR4) monoclonal antibody produced by mCCR4 N-terminal peptide immunization. C4Mab-1 is useful for flow cytometric analysis. In this study, we conducted the epitope mapping of C4Mab-1 using enzyme-linked immunosorbent assay (ELISA) and peptide blocking assay. The result of ELISA indicated that Thr7, Asp8, and Gln11 of mCCR4 are the critical amino acids for the C4Mab-1 binding. Furthermore, peptide blocking assay by flow cytometry showed that Thr7, Asp8, and Gln11 of mCCR4 are essential for C4Mab-1 binding to mCCR4-overexpressed Chinese hamster ovary-K1 (CHO/mCCR4) cells, and Val6, Thr9, and Thr10 are involved in the C4Mab-1 binding to CHO/mCCR4 cells. These results indicate that the critical binding epitope of C4Mab-1 includes Thr7, Asp8, and Gln11 of mCCR4.
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Affiliation(s)
- Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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7
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Rosenkilde MM, Tsutsumi N, Knerr JM, Kildedal DF, Garcia KC. Viral G Protein-Coupled Receptors Encoded by β- and γ-Herpesviruses. Annu Rev Virol 2022; 9:329-351. [PMID: 35671566 PMCID: PMC9584139 DOI: 10.1146/annurev-virology-100220-113942] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Herpesviruses are ancient large DNA viruses that have exploited gene capture as part of their strategy to escape immune surveillance, promote virus spreading, or reprogram host cells to benefit their survival. Most acquired genes are transmembrane proteins and cytokines, such as viral G protein-coupled receptors (vGPCRs), chemokines, and chemokine-binding proteins. This review focuses on the vGPCRs encoded by the human β- and γ-herpesviruses. These include receptors from human cytomegalovirus, which encodes four vGPCRs: US27, US28, UL33, and UL78; human herpesvirus 6 and 7 with two receptors: U12 and U51; Epstein-Barr virus with one: BILF1; and Kaposi's sarcoma-associated herpesvirus with one: open reading frame 74. We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from endogenous receptors. Finally, we briefly discuss the therapeutic targeting of vGPCRs as future treatment of acute and chronic herpesvirus infections. Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Mette M Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark;
| | - Naotaka Tsutsumi
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Julius M Knerr
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark;
| | | | - K Christopher Garcia
- Departments of Molecular and Cellular Physiology, and Structural Biology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA;
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8
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Hearing Loss Caused by HCMV Infection through Regulating the Wnt and Notch Signaling Pathways. Viruses 2021; 13:v13040623. [PMID: 33917368 PMCID: PMC8067389 DOI: 10.3390/v13040623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 01/27/2023] Open
Abstract
Hearing loss is one of the most prevalent sensory disabilities worldwide with huge social and economic burdens. The leading cause of sensorineural hearing loss (SNHL) in children is congenital cytomegalovirus (CMV) infection. Though the implementation of universal screening and early intervention such as antiviral or anti-inflammatory ameliorate the severity of CMV-associated diseases, direct and targeted therapeutics is still seriously lacking. The major hurdle for it is that the mechanism of CMV induced SNHL has not yet been well understood. In this review, we focus on the impact of CMV infection on the key players in inner ear development including the Wnt and Notch signaling pathways. Investigations on these interactions may gain new insights into viral pathogenesis and reveal novel targets for therapy.
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9
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De Groof TWM, Elder EG, Siderius M, Heukers R, Sinclair JH, Smit MJ. Viral G Protein-Coupled Receptors: Attractive Targets for Herpesvirus-Associated Diseases. Pharmacol Rev 2021; 73:828-846. [PMID: 33692148 DOI: 10.1124/pharmrev.120.000186] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Herpesviruses are ubiquitous pathogens that establish lifelong, latent infections in their host. Spontaneous reactivation of herpesviruses is often asymptomatic or clinically manageable in healthy individuals, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with multiple proliferative cardiovascular and post-transplant diseases. Herpesviruses encode viral G protein-coupled receptors (vGPCRs) that alter the host cell by hijacking cellular pathways and play important roles in the viral life cycle and these different disease settings. In this review, we discuss the pharmacological and signaling properties of these vGPCRs, their role in the viral life cycle, and their contribution in different diseases. Because of their prominent role, vGPCRs have emerged as promising drug targets, and the potential of vGPCR-targeting therapeutics is being explored. Overall, these vGPCRs can be considered as attractive targets moving forward in the development of antiviral, cancer, and/or cardiovascular disease treatments. SIGNIFICANCE STATEMENT: In the last decade, herpesvirus-encoded G protein-coupled receptors (GPCRs) have emerged as interesting drug targets with the growing understanding of their critical role in the viral life cycle and in different disease settings. This review presents the pharmacological properties of these viral receptors, their role in the viral life cycle and different diseases, and the emergence of therapeutics targeting viral GPCRs.
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Affiliation(s)
- Timo W M De Groof
- In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium (T.W.M.D.G.); Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (E.G.E., J.H.S.); Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (M.S., R.H., M.J.S.); and QVQ Holding B.V., Utrecht, The Netherlands (R.H.)
| | - Elizabeth G Elder
- In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium (T.W.M.D.G.); Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (E.G.E., J.H.S.); Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (M.S., R.H., M.J.S.); and QVQ Holding B.V., Utrecht, The Netherlands (R.H.)
| | - Marco Siderius
- In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium (T.W.M.D.G.); Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (E.G.E., J.H.S.); Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (M.S., R.H., M.J.S.); and QVQ Holding B.V., Utrecht, The Netherlands (R.H.)
| | - Raimond Heukers
- In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium (T.W.M.D.G.); Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (E.G.E., J.H.S.); Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (M.S., R.H., M.J.S.); and QVQ Holding B.V., Utrecht, The Netherlands (R.H.)
| | - John H Sinclair
- In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium (T.W.M.D.G.); Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (E.G.E., J.H.S.); Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (M.S., R.H., M.J.S.); and QVQ Holding B.V., Utrecht, The Netherlands (R.H.)
| | - Martine J Smit
- In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium (T.W.M.D.G.); Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (E.G.E., J.H.S.); Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (M.S., R.H., M.J.S.); and QVQ Holding B.V., Utrecht, The Netherlands (R.H.)
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10
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Kang X, Zhang R, Kwong TN, Lui RN, Wu WK, Sung JJ, Yu J, Wong SH. Serrated neoplasia in the colorectum: gut microbiota and molecular pathways. Gut Microbes 2021; 13:1-12. [PMID: 33382354 PMCID: PMC7781617 DOI: 10.1080/19490976.2020.1863135] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with different gene expression patterns. There are two major colorectal carcinogenesis pathways: conventional adenoma-carcinoma pathway and alternative serrated neoplasia pathway. Apart from the conventional pathway that is typically initiated by characteristic APC mutation and chromosomal instability, the serrated neoplasia pathway is mainly characterized by mutations of BRAF or KRAS, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Despite the malignant potential of serrated lesions, they can be easily overlooked during endoscopy screening and even in pathological assessment due to its anatomical location, morphology, and histological features. It has been shown that environmental factors especially the gut microbial composition play a key role in CRC pathogenesis. Thus, the preferential localization of serrated lesions in specific intestine areas suggest that niche-specific microbiota composition might intertwined with host genetic perturbations during the development of serrated lesions. Although serrated lesions and conventional adenomas are biologically different, most studies have focused on conventional adenomas, while the pathophysiology and role of microorganisms in the development of serrated lesions remain elusive. In this review, we discuss on the role of gut microbiota in the serrated neoplasia pathway of colorectal carcinogenesis and its specific clinical and molecular features, and summarize the potential mechanisms involved.
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Affiliation(s)
- Xing Kang
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ru Zhang
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Division of Gastroenterology, Department of Medicine, Shenzhen People’s Hospital, Shenzhen, China
| | - Thomas Ny Kwong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Rashid Ns Lui
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William Kk Wu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Joseph Jy Sung
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Sunny H Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
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11
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Jones IKA, Haese NN, Gatault P, Streblow ZJ, Andoh TF, Denton M, Streblow CE, Bonin K, Kreklywich CN, Burg JM, Orloff SL, Streblow DN. Rat Cytomegalovirus Virion-Associated Proteins R131 and R129 Are Necessary for Infection of Macrophages and Dendritic Cells. Pathogens 2020; 9:E963. [PMID: 33228102 PMCID: PMC7699341 DOI: 10.3390/pathogens9110963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/05/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins have roles in cellular signaling, migration, and transformation, as well as viral dissemination, tropism, latency and reactivation. Herein, we review the contribution of CMV-encoded chemokines and chemokine receptors to these processes, and further elucidate the viral tropism role of rat CMV (RCMV) R129 and R131. These homologues of the human CMV (HCMV)-encoded chemokines UL128 and UL130 are of particular interest because of their dual role as chemokines and members of the pentameric entry complex, which is required for entry into cell types that are essential for viral transmission and dissemination. The contributions of UL128 and UL130 to acceleration of solid organ transplant chronic rejection are poorly understood, and are in need of an effective in vivo model system to elucidate the phenomenon. We demonstrated similar molecular entry requirements for R129 and R131 in the rat cells, as observed for HCMV, and provided evidence that R129 and R131 are part of the viral entry complex required for entry into macrophages, dendritic cells, and bone marrow cells.
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Affiliation(s)
- Iris K. A. Jones
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Nicole N. Haese
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Philippe Gatault
- Renal Transplant Unit, 10 Boulevard Tonnellé, University Hospital of Tours, 37032 Tours, France;
| | - Zachary J. Streblow
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Takeshi F. Andoh
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA; (J.M.B.); (S.L.O.)
| | - Michael Denton
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Cassilyn E. Streblow
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Kiley Bonin
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Craig N. Kreklywich
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
| | - Jennifer M. Burg
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA; (J.M.B.); (S.L.O.)
| | - Susan L. Orloff
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA; (J.M.B.); (S.L.O.)
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Daniel N. Streblow
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA; (I.K.A.J.); (N.N.H.); (Z.J.S.); (T.F.A.); (M.D.); (C.E.S.); (K.B.); (C.N.K.)
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12
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Stragliotto G, Pantalone MR, Rahbar A, Söderberg-Nauclér C. Valganciclovir as Add-On to Standard Therapy in Secondary Glioblastoma. Microorganisms 2020; 8:microorganisms8101471. [PMID: 32987955 PMCID: PMC7599902 DOI: 10.3390/microorganisms8101471] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/28/2022] Open
Abstract
Patients with glioblastoma have a very poor prognosis despite aggressive therapeutic strategies. Cytomegalovirus has been detected in >90% of glioblastoma tumors. This virus can affect tumor progression and may represent a novel glioblastoma therapy target. We report, here, a retrospective survival analysis of patients with secondary glioblastoma who were treated with the anti-viral drug valganciclovir at Karolinska University Hospital in Stockholm. We performed survival analyses of eight patients with secondary glioblastoma who were treated with a standard dose of valganciclovir as an add-on to second-line therapy after their disease progression to glioblastoma. Thirty-six patients with secondary glioblastoma admitted during the same time period who received similar treatment and care served as contemporary controls. The patients treated with valganciclovir showed an increased median overall survival after progression to glioblastoma compared with controls (19.1 versus 12.7 months, p = 0.0072). This result indicates a potential positive effect of valganciclovir in secondary glioblastoma, which is in agreement with our previous observation that valganciclovir treatment improves the outcomes of patients with newly diagnosed glioblastoma. Larger randomized studies are warranted to prove this hypothesis.
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Affiliation(s)
- Giuseppe Stragliotto
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden; (G.S.); (A.R.)
- Division of Neurology, Karolinska University Hospital, 17177 Stockholm, Sweden
| | - Mattia Russel Pantalone
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden; (G.S.); (A.R.)
- Division of Neurology, Karolinska University Hospital, 17177 Stockholm, Sweden
- Correspondence: (M.R.P.); (C.S.-N.)
| | - Afsar Rahbar
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden; (G.S.); (A.R.)
- Division of Neurology, Karolinska University Hospital, 17177 Stockholm, Sweden
| | - Cecilia Söderberg-Nauclér
- Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, 17164 Stockholm, Sweden; (G.S.); (A.R.)
- Division of Neurology, Karolinska University Hospital, 17177 Stockholm, Sweden
- Correspondence: (M.R.P.); (C.S.-N.)
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The constitutive activity of the viral-encoded G protein-coupled receptor US28 supports a complex signalling network contributing to cancer development. Biochem Soc Trans 2020; 48:1493-1504. [PMID: 32779712 PMCID: PMC7458396 DOI: 10.1042/bst20190988] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/05/2020] [Accepted: 07/14/2020] [Indexed: 12/23/2022]
Abstract
US28 is a viral G protein-coupled receptor (GPCR) encoded by the human cytomegalovirus (HCMV). This receptor, expressed both during lytic replication and viral latency, is required for latency. US28 is binding to a wide variety of chemokines but also exhibits a particularly high constitutive activity robustly modulating a wide network of cellular pathways altering the host cell environment to benefit HCMV infection. Several studies suggest that US28-mediated signalling may contribute to cancer progression. In this review, we discuss the unique structural characteristics that US28 acquired through evolution that confer a robust constitutive activity to this viral receptor. We also describe the wide downstream signalling network activated by this constitutive activation of US28 and discuss how these signalling pathways may promote and support important cellular aspects of cancer.
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14
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Lv YL, Han FF, An ZL, Jia Y, Xuan LL, Gong LL, Zhang W, Ren LL, Yang S, Liu H, Liu LH. Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study. Intervirology 2020; 63:10-16. [PMID: 32772018 DOI: 10.1159/000506683] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 02/15/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND This study was planned to investigate the association betweenhuman cytomegalovirus (HCMV) infection and gastrointestinal cancer (GIC) risk, by undertaking a meta-analysis and case-control cross-sectional study. SUMMARY A cross-sectional study analysis of 160 GIC patients and 100 control subjects indicated significantly higher HCMV prevalence in GIC patients based on the HCMV IgM test. However, a similar analysis based on an IgG test revealed no significant relationship. Further meta-analysis of 11 studies, including 1,044 patients and 991 healthy subjects, displayed HCMV infection as an important risk factor for not only colorectal cancer occurrence and development based on a HCMV DNA test, but also for GIC based on a HCMV IgM test. However, the IgG test again displayed no significant relationship between HCMV infection and GIC occurrence. Key Message: Overall, our study revealed that HCMV infection is associated with an increased GIC risk. However, additional studies are warranted to elucidate the molecular mechanism underlying this association.
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Affiliation(s)
- Ya-Li Lv
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Fei-Fei Han
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhuo-Ling An
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yangjie Jia
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Ling-Ling Xuan
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Li-Li Gong
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Wen Zhang
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lu-Lu Ren
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Song Yang
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - He Liu
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Li-Hong Liu
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China,
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15
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Dunn DM, Munger J. Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection. Front Cell Infect Microbiol 2020; 10:384. [PMID: 32850483 PMCID: PMC7403205 DOI: 10.3389/fcimb.2020.00384] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/23/2020] [Indexed: 12/13/2022] Open
Abstract
Calcium signaling and the AMP-activated protein kinase (AMPK) signaling networks broadly regulate numerous aspects of cell biology. Human Cytomegalovirus (HCMV) infection has been found to actively manipulate the calcium-AMPK signaling axis to support infection. Many HCMV genes have been linked to modulating calcium signaling, and HCMV infection has been found to be reliant on calcium signaling and AMPK activation. Here, we focus on the cell biology of calcium and AMPK signaling and what is currently known about how HCMV modulates these pathways to support HCMV infection and potentially contribute to oncomodulation.
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Affiliation(s)
- Diana M Dunn
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, United States
| | - Joshua Munger
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, United States
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16
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van Senten JR, Bebelman MP, van Gasselt P, Bergkamp ND, van den Bor J, Siderius M, Smit MJ. Human Cytomegalovirus-Encoded G Protein-Coupled Receptor UL33 Facilitates Virus Dissemination via the Extracellular and Cell-to-Cell Route. Viruses 2020; 12:v12060594. [PMID: 32486172 PMCID: PMC7354556 DOI: 10.3390/v12060594] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Human cytomegalovirus (HCMV) encodes four G protein-coupled receptor (GPCR) homologs. Three of these receptors, UL78, US27 and US28, are known for their roles in HCMV dissemination and latency. Despite importance of its rodent orthologs for viral replication and pathogenesis, such a function is not reported for the HCMV-encoded GPCR UL33. Using the clinical HCMV strain Merlin, we show that UL33 facilitates both cell-associated and cell-free virus transmission. A UL33-deficient virus derivative revealed retarded virus spread, formation of less and smaller plaques, and reduced extracellular progeny during multi-cycle growth analysis in fibroblast cultures compared to parental virus. The growth of UL33-revertant, US28-deficient, and US28-revertant viruses were similar to parental virus under multistep growth conditions. UL33- and US28-deficient Merlin viruses impaired cell-associated virus spread to a similar degree. Thus, the growth defect displayed by the UL33-deficient virus but not the US28-deficient virus reflects UL33's contribution to extracellular transmission. In conclusion, UL33 facilitates cell-associated and cell-free spread of the clinical HCMV strain Merlin in fibroblast cultures.
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17
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van Senten JR, Fan TS, Siderius M, Smit MJ. Viral G protein-coupled receptors as modulators of cancer hallmarks. Pharmacol Res 2020; 156:104804. [PMID: 32278040 DOI: 10.1016/j.phrs.2020.104804] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022]
Abstract
Herpesviruses encode transmembrane G protein-coupled receptors (GPCRs), which share structural homology to human chemokine receptors. These viral GPCRs include KSHV-encoded ORF74, EBV-encoded BILF1, and HCMV-encoded US28, UL33, UL78 and US27. Viral GPCRs hijack various signaling pathways and cellular networks, including pathways involved in the so-called cancer hallmarks as defined by Hanahan and Weinberg. These hallmarks describe cellular characteristics crucial for transformation and tumor progression. The cancer hallmarks involve growth factor-independent proliferation, angiogenesis, avoidance of apoptosis, invasion and metastasis, metabolic reprogramming, genetic instability and immune evasion amongst others. The role of beta herpesviruses modulating these cancer hallmarks is clearly highlighted by the proliferative and pro-angiogenic phenotype associated with KSHV infection which is largely ascribed to the ORF74-mediated modulation of signaling networks in host cells. For HCMV and Epstein-Bar encoded GPCRs, oncomodulatory effects have been described which contribute to the cancer hallmarks, thereby enhancing oncogenic development. In this review, we describe the main signaling pathways controlling the hallmarks of cancer which are affected by the betaherpesvirus encoded GPCRs. Most prominent among these involve the JAK-STAT, PI(3)K-AKT, NFkB and MAPK signaling nodes. These insights are important to effectively target these viral GPCRs and their signaling networks in betaherpesvirus-associated malignancies.
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Affiliation(s)
- Jeffrey R van Senten
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands
| | - Tian Shu Fan
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands
| | - Marco Siderius
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands
| | - Martine J Smit
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
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18
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He Z, Chen L, Chen G, Smaldini P, Bongers G, Catalan-Dibene J, Furtado GC, Lira SA. Interleukin 1 beta and Matrix Metallopeptidase 3 Contribute to Development of Epidermal Growth Factor Receptor-Dependent Serrated Polyps in Mouse Cecum. Gastroenterology 2019; 157:1572-1583.e8. [PMID: 31470007 PMCID: PMC7006742 DOI: 10.1053/j.gastro.2019.08.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 08/02/2019] [Accepted: 08/21/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Transgenic mice (HBUS) that express the epidermal growth factor receptor (EGFR) ligand HBEGF (heparin-binding epidermal growth factor-like growth factor) and a constitutively active G protein-coupled receptor (US28) in intestinal epithelial cells develop serrated polyps in the cecum. Development of serrated polyps depends on the composition of the gut microbiota and is associated with bacterial invasion of the lamina propria, accompanied by induction of inflammation and up-regulation of interleukin 1 beta (IL1B) and matrix metalloproteinase (MMP) 3 in the cecum. We investigated the mechanisms by which these changes contribute to development of serrated polyps. METHODS We performed studies with C57BL/6 (control) and HBUS mice. To accelerate polyp development, we increased the exposure of the bacteria to the lamina propria by injecting HBUS mice with diphtheria toxin, which binds transgenic HBEGF expressed by the epithelial cells and causes apoptosis. Mice were given injections of IL1B-neutralizing antibody and the MMP inhibitor N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. Intestinal tissues were collected from mice and analyzed by histology, reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence, and flow cytometry. We examined fibroblast subsets in polyps using single-cell RNA sequencing. RESULTS Administration of diphtheria toxin to HBUS mice accelerated development of serrated polyps (95% of treated mice developed polyps before 100 days of age, compared with 53% given vehicle). IL1B stimulated subsets of platelet-derived growth factor receptor alpha+ (PDGRFA+) fibroblasts isolated from cecum, resulting in increased expression of MMP3. Neutralizing antibodies against IL1B or administration of the MMP inhibitor reduced the number of serrated polyps that formed in the HBUS mice. Single-cell RNA sequencing analysis showed subsets of fibroblasts in serrated polyps that express genes that regulate matrix fibroblasts and inflammation. CONCLUSIONS In studies of mice, we found that barrier breakdown and expression of inflammatory factors contribute to development of serrated polyps. Subsets of cecal PDGFRA+ fibroblasts are activated by release of IL1B from myeloid cells during the early stages of serrated polyp development. MMP3 produced by PDGFRA+ fibroblasts is important for serrated polyp development. Our findings confirm the functions of previously identified serrated polyp-associated molecules and indicate roles for immune and stromal cells in serrated polyp development.
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Affiliation(s)
- Zhengxiang He
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Lili Chen
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Grace Chen
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paola Smaldini
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gerold Bongers
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jovani Catalan-Dibene
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Glaucia C. Furtado
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sergio A. Lira
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Geisler J, Touma J, Rahbar A, Söderberg-Nauclér C, Vetvik K. A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity. Cancers (Basel) 2019; 11:cancers11121842. [PMID: 31766600 PMCID: PMC6966479 DOI: 10.3390/cancers11121842] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/13/2022] Open
Abstract
Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15-20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.
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Affiliation(s)
- Jürgen Geisler
- Department of Oncology, Akershus University Hospital (AHUS), 1478 Lørenskog, Norway; (J.G.); (J.T.)
- Institute of Clinical Medicine, University of Oslo, Campus Akershus University Hospital (AHUS), 1478 Lørenskog, Norway
| | - Joel Touma
- Department of Oncology, Akershus University Hospital (AHUS), 1478 Lørenskog, Norway; (J.G.); (J.T.)
- Institute of Clinical Medicine, University of Oslo, Campus Akershus University Hospital (AHUS), 1478 Lørenskog, Norway
- Department of Breast and Endocrine Surgery at Akershus University Hospital (AHUS), 1478 Lørenskog, Norway
| | - Afsar Rahbar
- Department of Medicine, Division of Microbial Pathogenesis, Bioclinicum, Karolinska Institutet, 17176 Stockholm, Sweden; (A.R.); (C.S.-N.)
- Department of Neurosurgery, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Cecilia Söderberg-Nauclér
- Department of Medicine, Division of Microbial Pathogenesis, Bioclinicum, Karolinska Institutet, 17176 Stockholm, Sweden; (A.R.); (C.S.-N.)
- Department of Neurosurgery, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Katja Vetvik
- Institute of Clinical Medicine, University of Oslo, Campus Akershus University Hospital (AHUS), 1478 Lørenskog, Norway
- Department of Breast and Endocrine Surgery at Akershus University Hospital (AHUS), 1478 Lørenskog, Norway
- Correspondence: ; Tel.: +47-95796638
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20
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Chen PY, Wu CYJ, Fang JH, Chen HC, Feng LY, Huang CY, Wei KC, Fang JY, Lin CY. Functional Change of Effector Tumor-Infiltrating CCR5 +CD38 +HLA-DR +CD8 + T Cells in Glioma Microenvironment. Front Immunol 2019; 10:2395. [PMID: 31649684 PMCID: PMC6794477 DOI: 10.3389/fimmu.2019.02395] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/24/2019] [Indexed: 11/13/2022] Open
Abstract
Human glioma facilitates an impaired anti-tumor immunity response, including defects in circulation of T lymphocytes. The level of CD8+ T-cell activation acts as an immune regulator associated with disease progression. However, little is known about the characteristics of peripheral and tumor-infiltrating CD8+ T cells in patients with glioma. In this study, we examined the level of CD8+ T-cell activation in a group of 143 patients with glioma and determined that peripheral CD3+ T cells decreased in accordance with disease severity. The patients' peripheral CD8+ T-cell populations were similar to that of healthy donors, and a small amount of CD8+ tumor-infiltrating lymphocytes was identified in glioma tissues. An increase in activated CD8+ T cells, characterized as CD38+HLA-DR+, and their association with disease progression were identified in the patients' peripheral blood and glioma, and shown to display enriched CCR5+ and TNFR2+ expression levels. Ex vivo examination of CD38+HLA-DR+CD8+ T cells indicated that this subset of cells displayed stronger secretion of IFN-γ and IL-2 before and after a 6-h stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin (ION) relative to healthy CD38+HLA-DR+CD8+ T cells, indicating the functional feasibility of CD38+HLA-DR+CD8+ T cells. Higher CCL5 protein and mRNA levels were identified in glioma tissues, which was consistent with the immunohistochemistry results revealing both CCL5 and CD38+HLA-DR+CD8+ T cell expression. Patients' CCR5+CD38+HLA-DR+CD8+ T cells were further validated and shown to display increases in CD45RA+CCR7- and T-bet+ accompanied by substantial CD107-a, IFN-γ, and Granzyme B levels in response to glioma cells.
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Affiliation(s)
- Pin-Yuan Chen
- Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Caren Yu-Ju Wu
- Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Jian-He Fang
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hsiu-Chi Chen
- Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Li-Ying Feng
- Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chiung-Yin Huang
- Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Kuo-Chen Wei
- Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jia-You Fang
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.,Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Department of Anesthesiology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chun-Yen Lin
- School of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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21
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van Senten JR, Bebelman MP, Fan TS, Heukers R, Bergkamp ND, van Gasselt P, Langemeijer EV, Slinger E, Lagerweij T, Rahbar A, Stigter-van Walsum M, Maussang D, Leurs R, Musters RJP, van Dongen GAMS, Söderberg-Nauclér C, Würdinger T, Siderius M, Smit MJ. The human cytomegalovirus-encoded G protein-coupled receptor UL33 exhibits oncomodulatory properties. J Biol Chem 2019; 294:16297-16308. [PMID: 31519750 DOI: 10.1074/jbc.ra119.007796] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 09/09/2019] [Indexed: 12/14/2022] Open
Abstract
Herpesviruses can rewire cellular signaling in host cells by expressing viral G protein-coupled receptors (GPCRs). These viral receptors exhibit homology to human chemokine receptors, but some display constitutive activity and promiscuous G protein coupling. Human cytomegalovirus (HCMV) has been detected in multiple cancers, including glioblastoma, and its genome encodes four GPCRs. One of these receptors, US28, is expressed in glioblastoma and possesses constitutive activity and oncomodulatory properties. UL33, another HCMV-encoded GPCR, also displays constitutive signaling via Gαq, Gαi, and Gαs proteins. However, little is known about the nature and functional effects of UL33-driven signaling. Here, we assessed UL33's signaling repertoire and oncomodulatory potential. UL33 activated multiple proliferative, angiogenic, and inflammatory signaling pathways in HEK293T and U251 glioblastoma cells. Notably, upon infection, UL33 contributed to HCMV-mediated STAT3 activation. Moreover, UL33 increased spheroid growth in vitro and accelerated tumor growth in different in vivo tumor models, including an orthotopic glioblastoma xenograft model. UL33-mediated signaling was similar to that stimulated by US28; however, UL33-induced tumor growth was delayed. Additionally, the spatiotemporal expression of the two receptors only partially overlapped in HCMV-infected glioblastoma cells. In conclusion, our results unveil that UL33 has broad signaling capacity and provide mechanistic insight into its functional effects. UL33, like US28, exhibits oncomodulatory properties, elicited via constitutive activation of multiple signaling pathways. UL33 and US28 might contribute to HCMV's oncomodulatory effects through complementing and converging cellular signaling, and hence UL33 may represent a promising drug target in HCMV-associated malignancies.
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Affiliation(s)
- Jeffrey R van Senten
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Maarten P Bebelman
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Tian Shu Fan
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Raimond Heukers
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Nick D Bergkamp
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Puck van Gasselt
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Ellen V Langemeijer
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Erik Slinger
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Tonny Lagerweij
- Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Afsar Rahbar
- Department of Medicine Solna, Microbial Pathogenesis Research Unit and Department of Neurology, Center for Molecular Medicine, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Marijke Stigter-van Walsum
- Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - David Maussang
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Rob Leurs
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - René J P Musters
- Department of Physiology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Guus A M S van Dongen
- Department of Radiology and Nuclear Medicine, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Cecilia Söderberg-Nauclér
- Department of Medicine Solna, Microbial Pathogenesis Research Unit and Department of Neurology, Center for Molecular Medicine, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Thomas Würdinger
- Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Marco Siderius
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
| | - Martine J Smit
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands
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22
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Nauclér CS, Geisler J, Vetvik K. The emerging role of human cytomegalovirus infection in human carcinogenesis: a review of current evidence and potential therapeutic implications. Oncotarget 2019; 10:4333-4347. [PMID: 31303966 PMCID: PMC6611507 DOI: 10.18632/oncotarget.27016] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022] Open
Abstract
It is well-established that infections with viruses harboring oncogenic potential increase the cancer risk. Virus induced oncogenic processes are influenced by a complex and unique combination of host and environmental risk factors that are currently not fully understood. Many of the oncogenic viruses exhibit a prolonged, asymptomatic latency after a primary infection, and cause cancer in only a minority of carriers. From an epidemiologic point of view, it is therefore difficult to determine their role in cancer development. However, recent evidence suggests a neoplastic potential of one additional ubiquitous virus; human Cytomegalovirus (HCMV). Emerging data presents HCMV as a plausible cancer-causing virus by demonstrating its presence in >90% of common tumor types, while being absent in normal tissue surrounding the tumor. HCMV targets many cell types in tumor tissues, and can cause all the ten proposed hallmarks of cancer. This virus exhibits cellular tumor-promoting and immune-evasive strategies, hijacks proangiogenic and anti-apoptotic mechanisms and induces immunosuppressive effects in the tumor micro-environment. Recognizing new cancer-causing mechanisms may increase the therapeutic potential and prophylactic options for virus associated cancer forms. Such approaches could limit viral spread, and promote anti-viral and immune controlling strategies if given as add on to standard therapy to potentially improve the prognosis of cancer patients. This review will focus on HCMV-related onco-viral mechanisms and the potential of HCMV as a new therapeutic target in HCMV positive cancer forms.
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Affiliation(s)
- Cecilia Söderberg Nauclér
- Department of Medicine, Unit of Microbial Pathogenesis, Center for Molecular Medicine, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital (AHUS), Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Katja Vetvik
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Breast and Endocrine Surgery, AHUS, Lørenskog, Norway
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23
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Human cytomegalovirus infection is correlated with enhanced cyclooxygenase-2 and 5-lipoxygenase protein expression in breast cancer. J Cancer Res Clin Oncol 2019; 145:2083-2095. [PMID: 31203442 PMCID: PMC6658585 DOI: 10.1007/s00432-019-02946-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 05/27/2019] [Indexed: 01/26/2023]
Abstract
Purpose While enhanced expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) and their derived metabolites is associated with breast cancer (BC) risk, the precise link between BC carcinogenesis and enhanced inflammatory activity remains to be clarified. Human Cytomegalovirus (HCMV) may induce expression of COX-2 and 5-LO and is frequently found in breast cancer biopsies. Thus, we investigated whether there is an association between HCMV proteins and expression of COX-2 and 5-LO in human BC tissue and BC cell lines. Materials and methods Paraffin embedded biopsies obtained from 49 patients with breast cancer and 26 tissue samples from adjacent, benign breast tissues were retrospectively examined for HCMV-immediate early (IE), HCMV-Late (LA), COX-2, and 5-LO proteins by immunohistochemistry. In vitro, uninfected and HCMV-infected BC cell lines were examined for COX-2 and 5-LO transcripts and proteins by PCR and flow cytometry. Results Extensive expression of COX-2, 5-LO and HCMV-IE proteins were preferentially detected in BC samples. We found a statistically significant concordant correlation between extensive HCMV-IE and COX-2 (P < 0.0001) as well as with HCMV-IE and 5-LO (P = 0.0003) in infiltrating BC. In vitro, HCMV infection induced COX-2 and 5-LO transcripts and COX-2 proteins in MCF-7 cells (P =0.008, P =0.018, respectively). In MDA-MB-231 cells that already had high base line levels of COX-2 expression, HCMV induced both COX-2 and 5-LO proteins but not transcripts. Conclusion Our findings demonstrate a significant correlation between extensive HCMV-IE protein expression and overexpression of COX-2 and 5-LO in human breast cancer. Electronic supplementary material The online version of this article (10.1007/s00432-019-02946-8) contains supplementary material, which is available to authorized users.
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24
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Adlere I, Sun S, Zarca A, Roumen L, Gozelle M, Viciano CP, Caspar B, Arimont M, Bebelman JP, Briddon SJ, Hoffmann C, Hill SJ, Smit MJ, Vischer HF, Wijtmans M, de Graaf C, de Esch IJP, Leurs R. Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. Eur J Med Chem 2018; 162:631-649. [PMID: 30476826 DOI: 10.1016/j.ejmech.2018.10.060] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/23/2018] [Accepted: 10/27/2018] [Indexed: 01/20/2023]
Abstract
Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.
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Affiliation(s)
- I Adlere
- Griffin Discoveries BV, Amsterdam, the Netherlands
| | - S Sun
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - A Zarca
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - L Roumen
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - M Gozelle
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06560, Ankara, Turkey
| | - C Perpiñá Viciano
- Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Friedrich-Schiller University Jena, Hans-Knöll-Strasse 2, 07745, Jena, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany
| | - B Caspar
- Division of Pharmacology, Physiology and Neuroscience and Centre of Membrane Proteins and Receptors (COMPARE), School of Life Sciences, University of Nottingham, Nottingham, NG7 2UH, UK
| | - M Arimont
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - J P Bebelman
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - S J Briddon
- Division of Pharmacology, Physiology and Neuroscience and Centre of Membrane Proteins and Receptors (COMPARE), School of Life Sciences, University of Nottingham, Nottingham, NG7 2UH, UK
| | - C Hoffmann
- Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Friedrich-Schiller University Jena, Hans-Knöll-Strasse 2, 07745, Jena, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany
| | - S J Hill
- Division of Pharmacology, Physiology and Neuroscience and Centre of Membrane Proteins and Receptors (COMPARE), School of Life Sciences, University of Nottingham, Nottingham, NG7 2UH, UK
| | - M J Smit
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - H F Vischer
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - M Wijtmans
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - C de Graaf
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - I J P de Esch
- Griffin Discoveries BV, Amsterdam, the Netherlands; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
| | - R Leurs
- Griffin Discoveries BV, Amsterdam, the Netherlands; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands.
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25
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Krishna BA, Miller WE, O'Connor CM. US28: HCMV's Swiss Army Knife. Viruses 2018; 10:E445. [PMID: 30127279 PMCID: PMC6116241 DOI: 10.3390/v10080445] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 08/08/2018] [Accepted: 08/17/2018] [Indexed: 12/13/2022] Open
Abstract
US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV.
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Affiliation(s)
- Benjamin A Krishna
- Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
| | - William E Miller
- Department of Molecular Genetics, Biochemistry, & Microbiology, University of Cincinnati, Cincinnati, OH 45267, USA.
| | - Christine M O'Connor
- Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
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26
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Xue M, Shi L, Wang W, Chen S, Wang L. An Overview of Molecular Profiles in Ulcerative Colitis-Related Cancer. Inflamm Bowel Dis 2018; 24:1883-1894. [PMID: 29945208 DOI: 10.1093/ibd/izy221] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Indexed: 12/16/2022]
Abstract
Ulcerative colitis (UC) is an independent risk factor of colorectal cancer (CRC). Both genetic and epigentic events induce a unique molecular profile during the development from UC to UC-related CRC (UCRC). These molecular changes play varied roles in DNA repair, immune response, cell metabolism, and interaction with the microbiota during the carcinogenesis process. This review will systmatically discuss the molecular characteristics of UCRC and point out the future perspectives in this research field.
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Affiliation(s)
- Meng Xue
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liuhong Shi
- Department of Ultrasound, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Weijia Wang
- Department of Cardiology, School of Medicine, the Johns Hopkins Hospital, Baltimore, Maryland
| | - Shujie Chen
- Department of Gastroenterology, Sir Runrun Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangjing Wang
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
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27
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Khanizadeh S, Hasanvand B, Esmaeil Lashgarian H, Almasian M, Goudarzi G. Interaction of viral oncogenic proteins with the Wnt signaling pathway. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2018; 21:651-659. [PMID: 30140402 PMCID: PMC6098952 DOI: 10.22038/ijbms.2018.28903.6982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 03/08/2018] [Indexed: 12/13/2022]
Abstract
It is estimated that up to 20% of all types of human cancers worldwide are attributed to viruses. The genome of oncogenic viruses carries genes that have protein products that act as oncoproteins in cell proliferation and transformation. The modulation of cell cycle control mechanisms, cellular regulatory and signaling pathways by oncogenic viruses, plays an important role in viral carcinogenesis. Different signaling pathways play a part in the carcinogenesis that occurs in a cell. Among these pathways, the Wnt signaling pathway plays a predominant role in carcinogenesis and is known as a central cellular pathway in the development of tumors. There are three Wnt signaling pathways that are well identified, including the canonical or Wnt/β-catenin dependent pathway, the noncanonical or β-catenin-independent planar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca2+ pathway. Most of the oncogenic viruses modulate the canonical Wnt signaling pathway. This review discusses the interaction between proteins of several human oncogenic viruses with the Wnt signaling pathway.
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Affiliation(s)
- Sayyad Khanizadeh
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
- Department of Virology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Banafsheh Hasanvand
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | | | - Mohammad Almasian
- Department of English Language, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Gholamreza Goudarzi
- Department of Microbiology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
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28
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Heukers R, Fan TS, de Wit RH, van Senten JR, De Groof TWM, Bebelman MP, Lagerweij T, Vieira J, de Munnik SM, Smits-de Vries L, van Offenbeek J, Rahbar A, van Hoorick D, Söderberg-Naucler C, Würdinger T, Leurs R, Siderius M, Vischer HF, Smit MJ. The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. Oncogene 2018; 37:4110-4121. [PMID: 29706656 PMCID: PMC6062493 DOI: 10.1038/s41388-018-0255-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 02/04/2018] [Accepted: 03/14/2018] [Indexed: 01/10/2023]
Abstract
Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251− and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.
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Affiliation(s)
- Raimond Heukers
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Tian Shu Fan
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Raymond H de Wit
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Jeffrey R van Senten
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Timo W M De Groof
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Maarten P Bebelman
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Tonny Lagerweij
- Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
| | - Joao Vieira
- Ablynx N.V., Technologiepark 21, Zwijnaarde, 9052, Belgium
| | - Sabrina M de Munnik
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Laura Smits-de Vries
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Jody van Offenbeek
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Afsar Rahbar
- Department of Medicine Solna, Experimental Cardiovascular Research Unit and Department of Medicine and Neurology, Center for Molecular Medicine, Karolinska Institute, Stockholm, 171 77, Sweden
| | | | - Cecilia Söderberg-Naucler
- Department of Medicine Solna, Experimental Cardiovascular Research Unit and Department of Medicine and Neurology, Center for Molecular Medicine, Karolinska Institute, Stockholm, 171 77, Sweden
| | - Thomas Würdinger
- Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
| | - Rob Leurs
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Marco Siderius
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Henry F Vischer
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands
| | - Martine J Smit
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands.
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The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis. Cancers (Basel) 2018; 10:cancers10040098. [PMID: 29601503 PMCID: PMC5923353 DOI: 10.3390/cancers10040098] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/28/2018] [Accepted: 03/29/2018] [Indexed: 12/11/2022] Open
Abstract
Epstein-Barr virus (EBV) is characterized by a bipartite life cycle in which latent and lytic stages are alternated. Latency is compatible with long-lasting persistency within the infected host, while lytic expression, preferentially found in oropharyngeal epithelial tissue, is thought to favor host-to-host viral dissemination. The clinical importance of EBV relates to its association with cancer, which we think is mainly a consequence of the latency/persistency mechanisms. However, studies in murine models of tumorigenesis/lymphomagenesis indicate that the lytic cycle also contributes to cancer formation. Indeed, EBV lytic expression is often observed in established cell lines and tumor biopsies. Within the lytic cycle EBV expresses a handful of immunomodulatory (BCRF1, BARF1, BNLF2A, BGLF5 & BILF1) and anti-apoptotic (BHRF1 & BALF1) proteins. In this review, we discuss the evidence supporting an abortive lytic cycle in which these lytic genes are expressed, and how the immunomodulatory mechanisms of EBV and related herpesviruses Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV) result in paracrine signals that feed tumor cells. An abortive lytic cycle would reconcile the need of lytic expression for viral tumorigenesis without relaying in a complete cycle that would induce cell lysis to release the newly formed infective viral particles.
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Teo WH, Chen HP, Huang JC, Chan YJ. Human cytomegalovirus infection enhances cell proliferation, migration and upregulation of EMT markers in colorectal cancer-derived stem cell-like cells. Int J Oncol 2017; 51:1415-1426. [PMID: 29048611 PMCID: PMC5642395 DOI: 10.3892/ijo.2017.4135] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence suggests a link between persistent human cytomegalovirus (HCMV) infection and cancer. Although the role of HCMV in cancer is still elusive, recent studies revealed the presence of HCMV nucleic acids and proteins in different cancer types such as glioblastoma, colorectal, breast, and prostate cancers, and neuroblastoma. Although HCMV may not be directly associated with the neoplastic transformation, the presence of HCMV DNA in the tumorous tissue has been associated with altered clinical outcomes in cancer patients. However, the mechanisms involved in the association between colorectal cancer (CRC) and HCMV are unclear. In this study, we investigated the influence of HCMV infection on CRC or their derived cells. Proliferation and migration assays revealed a high infection efficiency in CRC-derived HT29 and SW480 'stem-like' cells. After 24, 48 and 72 h of HCMV infection, both HT29 and SW480 parental and stem-like cells showed a significant increase in cell proliferation and viability (p<0.0001). Moreover, HCMV infection promoted cell migration. These results demonstrate a significant phenotypic alteration in the CRC cell line upon HCMV infection. Using epithelial to mesenchymal transition (EMT) assays, we demonstrated that the EMT markers and driver genes were upregulated during the virus infection. The WNT signaling pathway, which is associated with the proliferation and migration of CRC cells, was upregulated (6-fold) in HCMV-infected cells as compared to the non-infected cells at day 7 from infection.
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Affiliation(s)
- Wan Huai Teo
- Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Hsin-Pai Chen
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C
| | - Jason C Huang
- Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Yu-Jiun Chan
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C
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Lollinga WT, de Wit RH, Rahbar A, Vasse GF, Davoudi B, Diepstra A, Riezebos-Brilman A, Harmsen MC, Hillebrands JL, Söderberg-Naucler C, van Son WJ, Smit MJ, Sanders JS, van den Born J. Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro. Transplantation 2017; 101:531-540. [PMID: 27362315 DOI: 10.1097/tp.0000000000001289] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling. METHODS Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro. RESULTS Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller. CONCLUSIONS In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.
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Affiliation(s)
- Wouter T Lollinga
- 1 Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 2 Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, the Netherlands. 3 Department of Medicine, Center for Molecular Medicine, Unit for Microbial Pathogenesis, Karolinska Institutet, Solna, Stockholm, Sweden. 4 Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 5 Division of Clinical Virology, Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 6 Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Stegman JR, Margulies BJ. The human cytomegalovirus chemokine receptor homolog encoded by US27. Virus Genes 2017; 53:516-521. [DOI: 10.1007/s11262-017-1462-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/21/2017] [Indexed: 12/12/2022]
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33
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Arimont M, Sun SL, Leurs R, Smit M, de Esch IJP, de Graaf C. Structural Analysis of Chemokine Receptor-Ligand Interactions. J Med Chem 2017; 60:4735-4779. [PMID: 28165741 PMCID: PMC5483895 DOI: 10.1021/acs.jmedchem.6b01309] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
![]()
This
review focuses on the construction and application of structural chemokine
receptor models for the elucidation of molecular determinants of chemokine
receptor modulation and the structure-based discovery and design of
chemokine receptor ligands. A comparative analysis of ligand binding
pockets in chemokine receptors is presented, including a detailed
description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures,
and their implication for modeling molecular interactions of chemokine
receptors with small-molecule ligands, peptide ligands, and large
antibodies and chemokines. These studies demonstrate how the integration
of new structural information on chemokine receptors with extensive
structure–activity relationship and site-directed mutagenesis
data facilitates the prediction of the structure of chemokine receptor–ligand
complexes that have not been crystallized. Finally, a review of structure-based
ligand discovery and design studies based on chemokine receptor crystal
structures and homology models illustrates the possibilities and challenges
to find novel ligands for chemokine receptors.
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Affiliation(s)
- Marta Arimont
- Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
| | - Shan-Liang Sun
- Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
| | - Rob Leurs
- Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
| | - Martine Smit
- Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
| | - Iwan J P de Esch
- Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
| | - Chris de Graaf
- Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
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Lee S, Chung YH, Lee C. US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection. Biomol Ther (Seoul) 2017; 25:69-79. [PMID: 28035083 PMCID: PMC5207464 DOI: 10.4062/biomolther.2016.208] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 11/19/2016] [Accepted: 11/22/2016] [Indexed: 11/05/2022] Open
Abstract
Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.
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Affiliation(s)
- Sungjin Lee
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Yoon Hee Chung
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Choongho Lee
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
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35
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Cummings RJ, Barbet G, Bongers G, Hartmann BM, Gettler K, Muniz L, Furtado GC, Cho J, Lira SA, Blander JM. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 2016; 539:565-569. [PMID: 27828940 PMCID: PMC5807003 DOI: 10.1038/nature20138] [Citation(s) in RCA: 173] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 09/30/2016] [Indexed: 12/19/2022]
Abstract
Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions, are not merely extruded to maintain homeostatic cell numbers, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4+ T-cell activation. A common 'suppression of inflammation' signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4+ T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.
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Affiliation(s)
- Ryan J Cummings
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Gaetan Barbet
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Gerold Bongers
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Boris M Hartmann
- Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA
| | - Kyle Gettler
- Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA
| | - Luciana Muniz
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Glaucia C Furtado
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Judy Cho
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Sergio A Lira
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - J Magarian Blander
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
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36
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de Wit RH, Mujić-Delić A, van Senten JR, Fraile-Ramos A, Siderius M, Smit MJ. Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells. Oncotarget 2016; 7:67966-67985. [PMID: 27602585 PMCID: PMC5356532 DOI: 10.18632/oncotarget.11817] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 08/25/2016] [Indexed: 12/20/2022] Open
Abstract
The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays an important role by supporting proliferation, angiogenesis and reprogramming of energy metabolism. In this study we show that US28 signaling results in activation of the HIF-1α/PKM2 feedforward loop in fibroblasts and glioblastoma cells. The constitutive activity of US28 increases HIF-1 protein stability through a Gαq-, CaMKII- and Akt/mTOR-dependent mechanism. Furthermore, we found that VEGF and lactate secretion are increased and HIF-1 target genes, glucose transporter type 1 (GLUT1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), involved in glucose metabolism, are upregulated in US28 expressing cells. In addition, PKM2 is phosphorylated and found to be in a tumor-associated dimeric state upon US28 expression. Also in HCMV-infected cells HIF-1 activity is enhanced, which in part is US28-dependent. Finally, increased proliferation of cells expressing US28 is abolished upon inhibition of the HIF-1α/PKM2 cascade. These data highlight the importance of HIF-1α and PKM2 in US28-induced proliferation, angiogenesis and metabolic reprogramming.
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Affiliation(s)
- Raymond H. de Wit
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan, Amsterdam, The Netherlands
| | - Azra Mujić-Delić
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan, Amsterdam, The Netherlands
| | - Jeffrey R. van Senten
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan, Amsterdam, The Netherlands
| | - Alberto Fraile-Ramos
- Division of Cell Biology, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Marco Siderius
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan, Amsterdam, The Netherlands
| | - Martine J. Smit
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan, Amsterdam, The Netherlands
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37
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van Zuylen WJ, Rawlinson WD, Ford CE. The Wnt pathway: a key network in cell signalling dysregulated by viruses. Rev Med Virol 2016; 26:340-55. [PMID: 27273590 DOI: 10.1002/rmv.1892] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 05/04/2016] [Accepted: 05/12/2016] [Indexed: 12/19/2022]
Abstract
Viruses are obligate parasites dependent on host cells for survival. Viral infection of a cell activates a panel of pattern recognition receptors that mediate antiviral host responses to inhibit viral replication and dissemination. Viruses have evolved mechanisms to evade and subvert this antiviral host response, including encoding proteins that hijack, mimic and/or manipulate cellular processes such as the cell cycle, DNA damage repair, cellular metabolism and the host immune response. Currently, there is an increasing interest whether viral modulation of these cellular processes, including the cell cycle, contributes to cancer development. One cellular pathway related to cell cycle signalling is the Wnt pathway. This review focuses on the modulation of this pathway by human viruses, known to cause (or associated with) cancer development. The main mechanisms where viruses interact with the Wnt pathway appear to be through (i) epigenetic modification of Wnt genes; (ii) cellular or viral miRNAs targeting Wnt genes; (iii) altering specific Wnt pathway members, often leading to (iv) nuclear translocation of β-catenin and activation of Wnt signalling. Given that diverse viruses affect this signalling pathway, modulating Wnt signalling could be a generalised critical process for the initiation or maintenance of viral pathogenesis, with resultant dysregulation contributing to virus-induced cancers. Further study of this virus-host interaction may identify options for targeted therapy against Wnt signalling molecules as a means to reduce virus-induced pathogenesis and the downstream consequences of infection. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Wendy J van Zuylen
- Serology and Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia.,School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - William D Rawlinson
- Serology and Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia.,School of Medical Sciences, University of New South Wales, Sydney, Australia.,School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Caroline E Ford
- Metastasis Research Group, School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
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38
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Zhang J, Feng H, Xu S, Feng P. Hijacking GPCRs by viral pathogens and tumor. Biochem Pharmacol 2016; 114:69-81. [PMID: 27060663 DOI: 10.1016/j.bcp.2016.03.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 03/25/2016] [Indexed: 01/11/2023]
Abstract
G protein-coupled receptors (GPCRs) constitute the largest family of molecules that transduce signals across the plasma membrane. Herpesviruses are successful pathogens that evolved diverse mechanisms to benefit their infection. Several human herpesviruses express GPCRs to exploit cellular signaling cascades during infection. These viral GPCRs demonstrate distinct biochemical and biophysical properties that result in the activation of a broad spectrum of signaling pathways. In immune-deficient individuals, human herpesvirus infection and the expression of their GPCRs are implicated in virus-associated diseases and pathologies. Emerging studies also uncover diverse mutations in components, particularly GPCRs and small G proteins, of GPCR signaling pathways that render the constitutive activation of proliferative and survival signal, which contributes to the oncogenesis of various human cancers. Hijacking GPCR-mediated signaling is a signature shared by diseases associated with constitutively active viral GPCRs and cellular mutations activating GPCR signaling, exposing key molecules that can be targeted for anti-viral and anti-tumor therapy.
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Affiliation(s)
- Junjie Zhang
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, United States.
| | - Hao Feng
- Key Laboratory of Protein Chemistry and Fish Developmental Biology of Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
| | - Simin Xu
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, United States
| | - Pinghui Feng
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, United States.
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Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development. Proc Natl Acad Sci U S A 2016; 113:E2057-65. [PMID: 27006499 DOI: 10.1073/pnas.1603223113] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Mutations in SMAD4 predispose to the development of gastrointestinal cancer, which is the third leading cause of cancer-related deaths. To identify genes driving gastric cancer (GC) development, we performed a Sleeping Beauty (SB) transposon mutagenesis screen in the stomach of Smad4(+/-) mutant mice. This screen identified 59 candidate GC trunk drivers and a much larger number of candidate GC progression genes. Strikingly, 22 SB-identified trunk drivers are known or candidate cancer genes, whereas four SB-identified trunk drivers, including PTEN, SMAD4, RNF43, and NF1, are known human GC trunk drivers. Similar to human GC, pathway analyses identified WNT, TGF-β, and PI3K-PTEN signaling, ubiquitin-mediated proteolysis, adherens junctions, and RNA degradation in addition to genes involved in chromatin modification and organization as highly deregulated pathways in GC. Comparative oncogenomic filtering of the complete list of SB-identified genes showed that they are highly enriched for genes mutated in human GC and identified many candidate human GC genes. Finally, by comparing our complete list of SB-identified genes against the list of mutated genes identified in five large-scale human GC sequencing studies, we identified LDL receptor-related protein 1B (LRP1B) as a previously unidentified human candidate GC tumor suppressor gene. In LRP1B, 129 mutations were found in 462 human GC samples sequenced, and LRP1B is one of the top 10 most deleted genes identified in a panel of 3,312 human cancers. SB mutagenesis has, thus, helped to catalog the cooperative molecular mechanisms driving SMAD4-induced GC growth and discover genes with potential clinical importance in human GC.
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40
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Cai ZZ, Xu JG, Zhou YH, Zheng JH, Lin KZ, Zheng SZ, Ye MS, He Y, Liu CB, Xue ZX. Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer. World J Gastroenterol 2016; 22:2789-2798. [PMID: 26973417 PMCID: PMC4778001 DOI: 10.3748/wjg.v22.i9.2789] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/14/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess human cytomegalovirus-encoded US28 gene function in colorectal cancer (CRC) pathogenesis.
METHODS: Immunohistochemical analysis was performed to determine US28 expression in 103 CRC patient samples and 98 corresponding adjacent noncancerous samples. Patient data were compared by age, sex, tumor location, histological grade, Dukes’ stage, and overall mean survival time. In addition, the US28 gene was transiently transfected into the CRC LOVO cell line, and cell proliferation was assessed using a cell counting kit-8 assay. Cell cycle analysis by flow cytometry and a cell invasion transwell assay were also carried out.
RESULTS: US28 levels were clearly higher in CRC tissues (38.8%) than in adjacent noncancerous samples (7.1%) (P = 0.000). Interestingly, elevated US28 amounts in CRC tissues were significantly associated with histological grade, metastasis, Dukes’ stage, and overall survival (all P < 0.05); meanwhile, US28 expression was not significantly correlated with age, sex or tumor location. In addition, multivariate Cox regression data revealed US28 level as an independent CRC prognostic marker (P = 0.000). LOVO cells successfully transfected with the US28 gene exhibited higher viability, greater chemotherapy resistance, accelerated cell cycle progression, and increased invasion ability.
CONCLUSION: US28 expression is predictive of poor prognosis and may promote CRC.
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Ye MS, He Y, Yang SX, Lin H, Xue ZX, Cai ZZ. Clinical relevance between human cytomegalovirus infection and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:44-50. [DOI: 10.11569/wcjd.v24.i1.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the clinical relevance between human cytomegalovirus (HCMV) infection and colorectal cancer.
METHODS: The specific immunoglobulin G (IgG) and IgM antibodies against HCMV in sera of colorectal cancer patients (n = 60), patients with colorectal polyps (n = 60) and health controls (n = 60) were detected by chemiluminescence immunoassay. HCMV infection in colorectal cancer tissues and corresponding adjacent normal samples were determined through the detection of UL138 gene by nested PCR and in situ hybridization. The relationships between HCMV infection and clinical features of colorectal cancer were analyzed.
RESULTS: The positive rates of HCMV-IgG in the colorectal cancer group, colorectal polyps group and healthy control group were 95.0% (57/60), 98.3% (59/60), and 96.7% (58/60), respectively; the positive rates of HCMV-IgM were 5.0% (3/60), 1.7% (1/60) and 1.7% (1/60), respectively. There were no statistically significant differences in the positive rates of HCMV-IgG and HCMV-IgM among the three groups. However, there was a significant difference between colorectal cancer tissues and corresponding normal tissues in HCMV-UL138 detection. The positive rates of HCMV-UL138 were 65.6% (19/32) and 62.5% (20/32) in colorectal cancer tissues samples, and 12.5% (4/32) and 9.4% (3/32) in corresponding normal tissues as revealed by nested PCR detection and in situ hybridization, respectively. HCMV infection had no significant association with age, gender, location of mass, tumor size, histological differentiation, metastasis or Dukes stage.
CONCLUSION: HCMV infection is associated with colorectal cancer. Compared with corresponding normal epithelium, the neoplastic epithelium may be preferentially infected by the HCMV. This research suggests that HCMV infection may play a role in the occurrence and development of colorectal cancer.
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Cornaby C, Tanner A, Stutz EW, Poole BD, Berges BK. Piracy on the molecular level: human herpesviruses manipulate cellular chemotaxis. J Gen Virol 2015; 97:543-560. [PMID: 26669819 DOI: 10.1099/jgv.0.000370] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cellular chemotaxis is important to tissue homeostasis and proper development. Human herpesvirus species influence cellular chemotaxis by regulating cellular chemokines and chemokine receptors. Herpesviruses also express various viral chemokines and chemokine receptors during infection. These changes to chemokine concentrations and receptor availability assist in the pathogenesis of herpesviruses and contribute to a variety of diseases and malignancies. By interfering with the positioning of host cells during herpesvirus infection, viral spread is assisted, latency can be established and the immune system is prevented from eradicating viral infection.
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Affiliation(s)
- Caleb Cornaby
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA
| | - Anne Tanner
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA
| | - Eric W Stutz
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA
| | - Brian D Poole
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA
| | - Bradford K Berges
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA
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43
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Kumar A, Herbein G. Epigenetic regulation of human cytomegalovirus latency: an update. Epigenomics 2015; 6:533-46. [PMID: 25431945 DOI: 10.2217/epi.14.41] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Human cytomegalovirus (HCMV) is a ubiquitous virus which infects 50-90% of the population worldwide. In immunocompetent hosts, HCMV either remains unnoticed or causes mild symptoms. Upon primary infection it establishes latent infection in a few cells. However, in certain situations where immunity is either immature or compromised, HCMV may reactivate and cause mortality and morbidity. Therefore, it is utmost important to understand how HCMV establishes latent infection and associated mechanisms responsible for its reactivation. Several mechanisms are involved in the regulation of latency including chromatin remodeling by an array of enzymes and microRNAs. Here we will describe the epigenetic regulation of HCMV latency. Further we will discuss the unique HCMV latency signature and patho-physiological relevance of latent HCMV infection.
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Affiliation(s)
- Amit Kumar
- Department of Virology, University of Franche-Comte, CHRU Besançon, UPRES EA4266 Pathogens & Inflammation Department, SFR FED 4234, F-25030 Besançon, France
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Gianella S, Smith DM, Daar ES, Dube MP, Lisco A, Vanpouille C, Margolis L, Haubrich RH, Morris SR. Genital Cytomegalovirus Replication Predicts Syphilis Acquisition among HIV-1 Infected Men Who Have Sex with Men. PLoS One 2015; 10:e0130410. [PMID: 26061824 PMCID: PMC4465639 DOI: 10.1371/journal.pone.0130410] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 05/20/2015] [Indexed: 01/05/2023] Open
Abstract
Objective Sexually transmitted infections (STI) are common among HIV-infected men who have sex with men (MSM). While behavioral factors are important in STI acquisition, other biological factors such as immune modulation due to chronic viral infection may further predispose to STI acquisition. Design Post Hoc analysis including data collected over 12 months of follow-up from 131 HIV-infected MSM receiving antiretroviral therapy and screened for incident bacterial STI every 3 months. Methods Genital secretions collected at baseline were used to measure herpesvirus replication and inflammatory cytokines. Baseline predictors of STI were determined using survival analysis of time to incident STI. Results All participants were seropositive for cytomegalovirus (CMV), and 52% had detectable genital CMV at baseline. Thirty-five individuals acquired STI during follow-up, sometimes with multiple pathogen (17 syphilis, 21 gonorrhea, 14 chlamydia). Syphilis acquisition was associated with genital CMV replication at baseline (19.1% CMV-shedders versus 4.8% non-shedders, p=0.03) and younger age (p=0.02). Lower seminal MCP-1 was associated with higher seminal CMV levels and with syphilis acquisition (p<0.01). For syphilis acquisition, in multivariable Cox-Proportional Hazard model adjusted hazard rates were 3.56 (95%CI:1.00–12.73) for baseline CMV replication and 2.50 (0.92–6.77) for younger age. Conclusions This post hoc analysis suggest that CMV-associated decrease in seminal MCP-1 levels might predispose HIV-infected MSM to syphilis acquisition, but not other STI. Future studies should determine underlying mechanisms and if a causal association exists.
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Affiliation(s)
- Sara Gianella
- University of California, San Diego, La Jolla, California, United States of America
| | - Davey M Smith
- University of California, San Diego, La Jolla, California, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America
| | - Eric S Daar
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Michael P Dube
- University of Southern California Keck School of Medicine, Los Angeles, California, United States of America
| | - Andrea Lisco
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Christophe Vanpouille
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Leonid Margolis
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Richard H Haubrich
- University of California, San Diego, La Jolla, California, United States of America
| | - Sheldon R Morris
- University of California, San Diego, La Jolla, California, United States of America
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45
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Price RL, Chiocca EA. Modeling cytomegalovirus infection in mouse tumor models. Front Oncol 2015; 5:61. [PMID: 25853089 PMCID: PMC4362273 DOI: 10.3389/fonc.2015.00061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 02/25/2015] [Indexed: 12/31/2022] Open
Abstract
The hypothesis that cytomegalovirus (CMV) modulates cancer is evolving. Originally discovered in glioblastoma in 2002, the number of cancers, where intratumoral CMV antigen is detected, has increased in recent years suggesting that CMV actively affects the pathobiology of certain tumors. These findings are controversial as several groups have also reported inability to replicate these results. Regardless, several clinical trials for glioblastoma are underway or have been completed that target intratumoral CMV with anti-viral drugs or immunotherapy. Therefore, a better understanding of the possible pathobiology of CMV in cancer needs to be ascertained. We have developed genetic, syngeneic, and orthotopic malignant glioma mouse models to study the role of CMV in cancer development and progression. These models recapitulate for the most part intratumoral CMV expression as seen in human tumors. Additionally, we discovered that CMV infection in Trp53−/+ mice promotes pleomorphic rhabdomyosarcomas. These mouse models are not only a vehicle for studying pathobiology of the viral-tumor interaction but also a platform for developing and testing cancer therapeutics.
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Affiliation(s)
- Richard Lee Price
- Department of Neurological Surgery, Washington University , St. Louis, MO , USA
| | - Ennio Antonio Chiocca
- Harvey Cushing Neuro-Oncology Laboratories, Harvard Institutes of Medicine, Department of Neurosurgery and Institute for the Neurosciences, Brigham and Women's Faulkner Hospital and Center for Neuro-Oncology, Dana-Farber Cancer Institute , Boston, MA , USA
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46
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Joshi S, Wels C, Beham-Schmid C, Fukunaga-Kalabis M, Holmen SL, Otte M, Herlyn M, Waldhoer M, Schaider H. Gα13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma. Int J Cancer 2015; 137:1503-8. [PMID: 25754407 DOI: 10.1002/ijc.29506] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 02/12/2015] [Indexed: 11/09/2022]
Abstract
US28, a constitutively active G-protein-coupled receptor encoded by the human cytomegalovirus, leads to mechanistically unknown programmed cell death. Here we show that expression of wild-type US28 in human melanoma cells leads to apoptotic cell death via caspase 3 activation along with reduced cell proliferation. Reduced tumor growth upon US28 expression was observed in a xenograft mouse model. The signaling mute US28R129A showed a reduced antiproliferative effect. On evaluating different G-proteins coupled to US28 for signal transduction, Gα13 was identified as the main G-protein executing the apoptotic effect. Silencing of Gα13 but not Gαq resulted in a substantial increase in cell survival. Overexpression of Gα13 but not Gαq and their GTPase deficient forms Gα13Q226L and GαqQ209L, respectively, confirmed the requirement of Gα13 for US28 mediated cell death. Increasing expression of Gα13 alone induced cell death underscoring its relay function for US28 mediated decreased cell viability. Further reduced expression of Gα13 in melanoma cell lines isolated from advanced lesions and melanoma tissue was observed. These findings identified Gα13 as crucial for US28-induced cell death, substantiating that the effect of US28 on cell fate depends on preferred G-protein binding.
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Affiliation(s)
- Shripad Joshi
- Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.,Centre for Medical Research (ZMF), Medical University of Graz, Graz, Austria
| | - Christian Wels
- Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.,Centre for Medical Research (ZMF), Medical University of Graz, Graz, Austria
| | | | | | - Sheri L Holmen
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | | | | | - Maria Waldhoer
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.,Novo Nordisk a/S, Novo Nordisk Park, E5.2.18, Måløv, Denmark
| | - Helmut Schaider
- Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.,Centre for Medical Research (ZMF), Medical University of Graz, Graz, Austria.,Dermatology Research Centre, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.,The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
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47
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de Munnik SM, Smit MJ, Leurs R, Vischer HF. Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors. Front Pharmacol 2015; 6:40. [PMID: 25805993 PMCID: PMC4353375 DOI: 10.3389/fphar.2015.00040] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 02/12/2015] [Indexed: 12/22/2022] Open
Abstract
Human herpesviruses (HHVs) are widespread infectious pathogens that have been associated with proliferative and inflammatory diseases. During viral evolution, HHVs have pirated genes encoding viral G protein-coupled receptors (vGPCRs), which are expressed on infected host cells. These vGPCRs show highest homology to human chemokine receptors, which play a key role in the immune system. Importantly, vGPCRs have acquired unique properties such as constitutive activity and the ability to bind a broad range of human chemokines. This allows vGPCRs to hijack human proteins and modulate cellular signaling for the benefit of the virus, ultimately resulting in immune evasion and viral dissemination to establish a widespread and lifelong infection. Knowledge on the mechanisms by which herpesviruses reprogram cellular signaling might provide insight in the contribution of vGPCRs to viral survival and herpesvirus-associated pathologies.
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Affiliation(s)
- Sabrina M de Munnik
- Amsterdam Institute for Molecules Medicines and Systems - Division of Medicinal Chemistry, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, Amsterdam Netherlands
| | - Martine J Smit
- Amsterdam Institute for Molecules Medicines and Systems - Division of Medicinal Chemistry, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, Amsterdam Netherlands
| | - Rob Leurs
- Amsterdam Institute for Molecules Medicines and Systems - Division of Medicinal Chemistry, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, Amsterdam Netherlands
| | - Henry F Vischer
- Amsterdam Institute for Molecules Medicines and Systems - Division of Medicinal Chemistry, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, Amsterdam Netherlands
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48
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Rahbar A, Peredo I, Solberg NW, Taher C, Dzabic M, Xu X, Skarman P, Fornara O, Tammik C, Yaiw K, Wilhelmi V, Assinger A, Stragliotto G, Söderberg-Naucler C. Discordant humoral and cellular immune responses to Cytomegalovirus (CMV) in glioblastoma patients whose tumors are positive for CMV. Oncoimmunology 2015; 4:e982391. [PMID: 25949880 DOI: 10.4161/2162402x.2014.982391] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 10/28/2014] [Indexed: 01/22/2023] Open
Abstract
Background. Glioblastoma (GBM) is the most common malignant brain tumor in adults and is nearly always fatal. Emerging evidence suggests that human Cytomegalovirus (HCMV) is present in 90-100% of GBMs and that add-on antiviral treatment for HCMV show promise to improve survival. Methods. In a randomized, placebo-controlled trial of valganciclovir in 42 GBM patients, blood samples were collected for analyses of HCMV DNA, RNA, reactivity against HCMV peptides, IgG, and IgM at baseline and at 3, 12, and 24 weeks of treatment. Results. All 42 tumors were positive for HCMV protein. All patients examined had at least one blood sample positive for HCMV DNA, 63% were HCMV RNA positive, and 21% were IgM positive. However, 29% of GBM patients were IgG negative for HCMV. Five of these samples were positive in an enzyme-linked immunosorbent assay (ELISA) that used antigens derived from a clinical isolate. Blood T cells from 11 of 13 (85%) HCMV IgG-negative GBM patients reacted against HCMV peptides. Valganciclovir did not affect IgG titers, DNA, or RNA levels of the HCMV immediate early (HCMV IE) gene in blood. Conclusion. In GBM patients, HCMV activity is higher than in healthy controls and serology is a poor test to define previous or active HCMV infection in these patients.
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Key Words
- ELISA, enzyme-linked immunosorbent assay
- FACS, flow cytometry analyses
- FITC, fluorescein isothiocyanate
- GBM, glioblastoma
- HCMV IE, human Cytomegalovirus-immediate early
- HCMV, human Cytomegalovirus
- HIV, human immunodeficiency virus
- HSV, herpes simplex virus
- PBMC, Peripheral blood mononuclear cells
- PBS, Phosphate buffered saline
- PCR, polymerase chain reaction
- SEB, staphylococcal snterotoxin B
- VIGAS study, Efficacy and Safety of Valcyte® as an Add-on Therapy in Patients with Malignant Glioblastoma and cytomegalovirus infection
- Valcyte
- cytomegalovirus
- glioblastoma
- peptides stimulation
- serology
- valganciclovir
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Affiliation(s)
- Afsar Rahbar
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Inti Peredo
- Departments of Neurosurgery; Karolinska University Hospital ; Stockholm, Sweden
| | - Nina Wolmer Solberg
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Chato Taher
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Mensur Dzabic
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Xinling Xu
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Petra Skarman
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Olesja Fornara
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Charlotte Tammik
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Koon Yaiw
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Vanessa Wilhelmi
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | - Alice Assinger
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
| | | | - Cecilia Söderberg-Naucler
- Department of Medicine; Solna; Center for Molecular Medicine; Karolinska Institute ; Stockholm, Sweden
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49
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Söderberg-Nauclér C, Johnsen JI. Cytomegalovirus in human brain tumors: Role in pathogenesis and potential treatment options. World J Exp Med 2015; 5:1-10. [PMID: 25699229 PMCID: PMC4308527 DOI: 10.5493/wjem.v5.i1.1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 11/13/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
During the last years increasing evidence implies that human cytomegalovirus (CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.
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50
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Abstract
In 1908, Oluf Bang and Vilhelm Ellerman laid the foundation for theory of oncoviruses by demonstrating that the avian erythroblastosis (a form of chicken leukaemia) could be transmitted by cell-free extracts. Since then, it has been shown very convincingly that viruses can directly cause several human cancers by various mechanisms. Epidemiological data imply that viruses are the second most important risk factor for cancer development in humans, exceeded only by tobacco consumption. Although the ability of certain viruses (hepatitis B and C, human papillomavirus, etc) to cause cancer has been time tested and proven scientifically, there are several other potential viral candidates whose role in oncogenesis is more controversial. One such controversial scenario involves the role of cytomegalovirus (CMV) in malignant gliomas, the most common form of primary brain tumour. CMV first attracted attention about a decade ago when CMV gene products were found in glioma tissue but not in normal brain. Since this initial observation, several different groups have shown an oncomodulatory effect of CMV; however, direct association between CMV infection and incidence of glioma is lacking. In this review, we will evaluate the evidence, both preclinical and clinical, regarding the possible role of CMV in gliomagenesis and maintenance. We will also critically evaluate the rationale for using antiviral drugs in the treatment of patients with glioma.
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Affiliation(s)
- Mahua Dey
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
| | - Atique U Ahmed
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
| | - Maciej S Lesniak
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
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