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Xiao Q, Liu Y, Shu X, Li Y, Zhang X, Wang C, He S, Li J, Li T, Liu T, Liu Y. Molecular mechanisms of viral oncogenesis in haematological malignancies: perspectives from metabolic reprogramming, epigenetic regulation and immune microenvironment remodeling. Exp Hematol Oncol 2025; 14:69. [PMID: 40349096 PMCID: PMC12065340 DOI: 10.1186/s40164-025-00655-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 04/13/2025] [Indexed: 05/14/2025] Open
Abstract
Haematological malignancies are one of the most common tumors, with a rising incidence noted over recent decades. Viral infections play significant roles in the pathogenesis of these malignancies globally. This review delves into the contributions of various known viruses-specifically Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), human cytomegalovirus (HCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human papillomavirus (HPV)-in the development of haematological malignancies. These viruses are shown to drive tumorigenesis through mechanisms, such as metabolic reprogramming, epigenetic modifications, and remodeling of the immune microenvironment. By directly disrupting fundamental cellular functions and altering metabolic and epigenetic pathways, these viruses foster an immune milieu that supports both viral persistence and tumor growth. A thorough understanding of these viral oncogenic processes is crucial not only for etiological discovery but also for developing targeted interventions. This review emphasizes the need for continued research into the specific ways these viruses manipulate the host cell's metabolic and epigenetic environments, aiming to provide insights that could guide future advancements in treatment modalities.
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Affiliation(s)
- Qing Xiao
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Yi Liu
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Xuejiao Shu
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Ya Li
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Xiaomei Zhang
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Chaoyu Wang
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Sanxiu He
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Jun Li
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Tingting Li
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Tingting Liu
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Yao Liu
- Department of Hematology-Oncology, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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Kokudo T, Kokudo N. Impact of hepatitis C virus infection control on preventing the postoperative recurrence of intrahepatic cholangiocarcinoma. Hepatol Res 2025; 55:629-630. [PMID: 40318092 DOI: 10.1111/hepr.14182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Affiliation(s)
- Takashi Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
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Haas CB, Shiels MS, Pfeiffer RM, D’Arcy M, Luo Q, Yu K, Austin AA, Cohen C, Miller P, Morawski BM, Pawlish K, Robinson WT, Engels EA. Cancers with epidemiologic signatures of viral oncogenicity among immunocompromised populations in the United States. J Natl Cancer Inst 2024; 116:1983-1991. [PMID: 38954841 PMCID: PMC11630524 DOI: 10.1093/jnci/djae159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV and solid organ transplant recipients, 2 immunosuppressed populations, may help identify novel etiologic relationships with infectious agents. METHODS We used 2 linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified according to site and histology codes. Standardized incidence ratios were used to compare risk in people with HIV and solid organ transplant recipients with the general population. For selected cancer entities, incidence rate ratios were calculated for indicators of immunosuppression within each population. RESULTS We identified 38 047 cancer cases in solid organ transplant recipients and 53 592 in people with HIV, yielding overall standardized incidence ratios of 1.66 (95% confidence interval [CI] = 1.65 to 1.68) and 1.49 (95% CI = 1.47 to 1.50), respectively. A total of 43 cancer entities met selection criteria, including conjunctival squamous cell carcinoma (people with HIV standardized incidence ratio = 7.1, 95% CI = 5.5 to 9.2; solid organ transplant recipients standardized incidence ratio = 9.4, 95% CI = 6.8 to 12.6). Sebaceous adenocarcinoma was elevated in solid organ transplant recipients (standardized incidence ratio = 16.2, 95% CI = 14.0 to 18.6) and, among solid organ transplant recipients, associated with greater risk in lung and heart transplant recipients compared with recipients of other organs (incidence rate ratio = 2.3, 95% CI = 1.7 to 3.2). Salivary gland tumors, malignant fibrous histiocytoma, and intrahepatic cholangiocarcinoma showed elevated risk in solid organ transplant recipients (standardized incidence ratio = 3.9, 4.7, and 3.2, respectively) but not in people with HIV. However, risks for these cancers were elevated following an AIDS diagnosis among people with HIV (incidence rate ratio = 2.4, 4.3, and 2.0, respectively). CONCLUSIONS Elevated standardized incidence ratios among solid organ transplant recipients and people with HIV, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival squamous cell carcinoma, sebaceous adenocarcinoma, salivary gland tumors, malignant fibrous histiocytoma, and intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Cameron B Haas
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Meredith S Shiels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Monica D’Arcy
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Qianlai Luo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Kelly Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | | | - Colby Cohen
- Florida Department of Health, Tallahassee, FL, USA
| | - Paige Miller
- Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, TX, USA
| | | | | | | | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
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Li J, Vranjkovic A, Read D, Delaney SP, Stanford WL, Cooper CL, Crawley AM. Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction. Front Immunol 2024; 15:1375485. [PMID: 38887299 PMCID: PMC11180750 DOI: 10.3389/fimmu.2024.1375485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/19/2024] [Indexed: 06/20/2024] Open
Abstract
Background The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. Methods RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. Results In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. Conclusions This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.
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Affiliation(s)
- Jiafeng Li
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
| | - Agatha Vranjkovic
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Daniel Read
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Sean P. Delaney
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - William L. Stanford
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Curtis L. Cooper
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Angela M. Crawley
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada
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Cheo FY, Chan KS, Shelat VG. Outcomes of liver resection in hepatitis C virus-related intrahepatic cholangiocarcinoma: A systematic review and meta-analysis. World J Virol 2024; 13:88946. [PMID: 38616852 PMCID: PMC11008402 DOI: 10.5501/wjv.v13.i1.88946] [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] [Received: 10/16/2023] [Revised: 11/10/2023] [Accepted: 12/28/2023] [Indexed: 03/11/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma is the second most common primary liver malignancy. Its incidence and mortality rates have been increasing in recent years. Hepatitis C virus (HCV) infection is a risk factor for development of cirrhosis and cholangiocarcinoma. Currently, surgical resection remains the only curative treatment option for cholangiocarcinoma. We aim to study the impact of HCV infection on outcomes of liver resection (LR) in intrahepatic cholangiocarcinoma (ICC). AIM To study the outcomes of curative resection of ICC in patients with HCV (i.e., HCV+) compared to patients without HCV (i.e., HCV-). METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies to assess the outcomes of LR in ICC in HCV+ patients compared to HCV- patients in tertiary care hospitals. PubMed, EMBASE, The Cochrane Library and Scopus were systematically searched from inception till August 2023. Included studies were RCTs and non-RCTs on patients ≥ 18 years old with a diagnosis of ICC who underwent LR, and compared outcomes between patients with HCV+ vs HCV-. The primary outcomes were overall survival (OS) and recurrence-free survival. Secondary outcomes include perioperative mortality, operation duration, blood loss, intrahepatic and extrahepatic recurrence. RESULTS Seven articles, published between 2004 and 2021, fulfilled the selection criteria. All of the studies were retrospective studies. Age, incidence of male patients, albumin, bilirubin, platelets, tumor size, incidence of multiple tumors, vascular invasion, bile duct invasion, lymph node metastases, and stage 4 disease were comparable between HCV+ and HCV- group. Alanine transaminase [MD 22.20, 95%confidence interval (CI): 13.75, 30.65, P < 0.00001] and aspartate transaminase levels (MD 27.27, 95%CI: 20.20, 34.34, P < 0.00001) were significantly higher in HCV+ group compared to HCV- group. Incidence of cirrhosis was significantly higher in HCV+ group [odds ratio (OR) 5.78, 95%CI: 1.38, 24.14, P = 0.02] compared to HCV- group. Incidence of poorly differentiated disease was significantly higher in HCV+ group (OR 2.55, 95%CI: 1.34, 4.82, P = 0.004) compared to HCV- group. Incidence of simultaneous hepatocellular carcinoma lesions was significantly higher in HCV+ group (OR 8.31, 95%CI: 2.36, 29.26, P = 0.001) compared to HCV- group. OS was significantly worse in the HCV+ group (hazard ratio 2.05, 95%CI: 1.46, 2.88, P < 0.0001) compared to HCV- group. CONCLUSION This meta-analysis demonstrated significantly worse OS in HCV+ patients with ICC who underwent curative resection compared to HCV- patients.
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Affiliation(s)
- Feng Yi Cheo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Kai Siang Chan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Vishal G Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Dutta RK, Jun J, Du K, Diehl AM. Hedgehog Signaling: Implications in Liver Pathophysiology. Semin Liver Dis 2023; 43:418-428. [PMID: 37802119 DOI: 10.1055/a-2187-3382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/08/2023]
Abstract
The purpose of this review is to summarize current knowledge about the role of the Hedgehog signaling pathway in liver homeostasis and disease. Hedgehog is a morphogenic signaling pathway that is active in development. In most healthy tissues, pathway activity is restricted to stem and/or stromal cell compartments, where it enables stem cell self-renewal and tissue homeostasis. Aberrant over-activation of Hedgehog signaling occurs in many cancers, including hepatocellular and cholangio-carcinoma. The pathway is also activated transiently in stromal cells of injured tissues and orchestrates normal wound healing responses, including inflammation, vascular remodeling, and fibrogenesis. In liver, sustained Hedgehog signaling in stromal cells plays a major role in the pathogenesis of cirrhosis. Hedgehog signaling was thought to be silenced in healthy hepatocytes. However, recent studies show that targeted disruption of the pathway in hepatocytes dysregulates lipid, cholesterol, and bile acid metabolism, and promotes hepatic lipotoxicity, insulin resistance, and senescence. Hepatocytes that lack Hedgehog activity also produce a secretome that activates Hedgehog signaling in cholangiocytes and neighboring stromal cells to induce inflammatory and fibrogenic wound healing responses that drive progressive fibrosis. In conclusion, Hedgehog signaling must be precisely controlled in adult liver cells to maintain liver health.
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Affiliation(s)
| | - JiHye Jun
- Department of Medicine, Duke University, Durham, North Carolina
| | - Kuo Du
- Department of Medicine, Duke University, Durham, North Carolina
| | - Anna Mae Diehl
- Department of Medicine, Duke University, Durham, North Carolina
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Catalano T, Selvaggi F, Esposito DL, Cotellese R, Aceto GM. Infectious Agents Induce Wnt/β-Catenin Pathway Deregulation in Primary Liver Cancers. Microorganisms 2023; 11:1632. [PMID: 37512809 PMCID: PMC10386003 DOI: 10.3390/microorganisms11071632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/18/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Interaction between infectious agents and liver tissue, as well as repeated and extreme biological events beyond adaptive capacities, may result in pathological conditions predisposing people to development of primary liver cancers (PLCs). In adults, PLCs mainly comprise hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Various infectious agents in the hepatic microenvironment can destabilize normal liver cell functions by modulating the Wnt/β-catenin pathway components. Among them, hepatotropic viruses B, C, and D are involved in Wnt/β-catenin signaling dysregulation. Other microbial agents, including oncogenic viruses such as Epstein-Barr virus (EBV) and human papilloma virus (HPV), bacteria, e.g., Mycoplasma hyorhinis and Salmonella Typhi, the protozoan parasite Toxoplasma gondii, the fungus Aspergillus flavus, and liver flukes such as Clonorchissinensis or Opisthorchis viverrini, may induce malignant transformation in hepatocytes or in target cells of the biliary tract through aberrant Wnt signaling activation. This review focuses on new insights into infectious agents implicated in the deregulation of Wnt signaling and PLC development. Since the Wnt/β-catenin pathway is a driver of cancer following viral and bacterial infections, molecules inhibiting the complex axis of Wnt signaling could represent novel therapeutic approaches in PLC treatment.
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Affiliation(s)
- Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Federico Selvaggi
- Unit of General Surgery, ASL2 Lanciano-Vasto-Chieti, Ospedale Clinicizzato SS Annunziata, 66100 Chieti, Italy;
| | - Diana Liberata Esposito
- Center for Advanced Studies and Technology (CAST), 66100 Chieti, Italy;
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
- Villa Serena Foundation for Research, 65013 Città Sant’Angelo, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
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Zhang L, Wang X, Ming A, Tan W. Pseudotyped Virus for Flaviviridae. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1407:313-327. [PMID: 36920705 DOI: 10.1007/978-981-99-0113-5_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Members of Flaviviridae are enveloped single positive-stranded RNA viruses including hepacivirus, pestivirus, pegivirus, and mosquito-transmitted flavivirus, which are important pathogens of infectious diseases and pose serious threats to human health. Pseudotyped virus is an artificially constructed virus-like particle, which could infect host cells similar to a live virus but cannot produce infectious progeny virus. Therefore, pseudotyped virus has the advantages of a wide host range, high transfection efficiency, low biosafety risk, and accurate and objective quantification. It has been widely used in biological characteristics, drug screening, detection methods, and vaccine evaluation of Flaviviridae viruses like hepatitis C virus, Japanese encephalitis virus, dengue virus, and Zika virus.
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Affiliation(s)
- Leiliang Zhang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xiao Wang
- Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Annan Ming
- Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Wenjie Tan
- NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
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Favourable outcome of acute hepatitis E infection in patients with ANCA-associated vasculitis. Orphanet J Rare Dis 2022; 17:433. [PMID: 36514177 PMCID: PMC9746154 DOI: 10.1186/s13023-022-02586-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 11/22/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is a frequent cause of acute viral hepatitis. Immunocompromised patients are at increased risk for viral infection and chronic courses of hepatitis. Whether patients with autoimmune diseases are at risk of developing clinically relevant hepatitis or even chronic liver disease after HEV infection is discussed controversially. ANCA-associated vasculitis is a rare autoimmune disease with potentially life-threatening organ involvement, thus requiring intensive immunosuppression with glucocorticoids, cyclophosphamide, or rituximab. As there are no reports available on the infection with HEV in patients with ANCA-associated vasculitis, clinical decision making in such cases is based on experiences from other disease entities. Therefore, in this study we analyzed the course of liver disease and the therapeutic management of autoimmune vasculitis in a retrospective cohort of five patients with ANCA-associated vasculitis and acute hepatitis E. RESULTS Four patients were on immunosuppressive maintenance therapy and one patient was on remission induction therapy with cyclophosphamide and high dose glucocorticoids. All patients had at least one potentially hepatotoxic co-medication at the time of hepatitis. Hepatitis-associated clinical symptoms were recorded in four of five patients. The course of hepatitis was characterized by strongly elevated transaminases, a temporary liver failure was observed in one case. The management of hepatitis E included cessation of the immunosuppressants in all patients, whereas oral glucocorticoids were not discontinued. Under this regime, all patients cleared the virus without additional anti-viral treatment. Liver enzymes normalized one month after they peaked. In the follow-up period of at least 1.5 years (range 1.5-12 years), no chronic liver disease was observed, although one patient died of cholangiocarcinoma with liver metastases some years after HEV infection. Vasculitis was not active in our patient cohort at the time of HEV infection. However, inflammatory flares occured in three of five patients after discontinuation of the immunosuppressive therapy. Immunosuppressants were paused for a median time of 4 weeks and after their resumption vasculitic disease activity was controlled in all patients. CONCLUSIONS Acute HEV infection in patients with ANCA-associated vasculitis shows a favorable outcome of liver disease but bears the risk of inflammatory flares due to cessation of immunosuppression.
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Sarantis P, Trifylli EM, Koustas E, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors. Int J Mol Sci 2022; 23:13612. [PMID: 36362398 PMCID: PMC9655697 DOI: 10.3390/ijms232113612] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
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Affiliation(s)
- Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Lin CR, Lee YK, Chiang CJ, Yang YW, Chang HC, You SL. Secular trends of intrahepatic cholangiocarcinoma in a high endemic area: A population-based study. World J Gastroenterol 2022; 28:3695-3705. [PMID: 36161044 PMCID: PMC9372811 DOI: 10.3748/wjg.v28.i28.3695] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/30/2022] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignancies. However, because of its scarcity there are limited population-based data available for investigations into its epidemiologic characteristics. In Taiwan, we have a national cancer registry database that can be used to evaluate the secular trends of ICC.
AIM To evaluate secular trends of ICC according to age, sex, and risk factors in Taiwan.
METHODS In this population-based study, we used the national Taiwan Cancer Registry database. Age-standardized and relative percent changes in incidence rates were used to describe secular trends in incidence rates and sex ratios of ICC in Taiwan.
RESULTS The age-standardized ICC incidence rate among males increased from 1.51 per 100000 in 1993-1997 to 4.07 per 100000 in 2013-2017 and among female from 1.73 per 100000 to 2.95 per 100000. The incidence in females tended to plateau after 2008-2012. For males, the ICC incidence increased as age increased. In the long-term incidence trend of ICC in females, the incidence of the four age groups (40-44, 45-49, 50-54 and 55-59 years) remained stable in different years; although, the incidence of the 60-64 group had a peak in 2003-2007, and the peak incidence of the 65-69 and 70-74 groups occurred in 2008-2012. Among males, beginning at the age of 65, there were increases in the incidence of ICC for the period of 2003-2017 as compared with females in the period of 2003-2017.
CONCLUSION Increased incidence of ICC occurred in Taiwan over the past two decades. The increased incidence has progressively shifted toward younger people for both males and females.
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Affiliation(s)
- Chun-Ru Lin
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242008, Taiwan
| | - Yu-Kwang Lee
- Department of Surgery, National Taiwan University Hospital, Taipei 100229, Taiwan
| | - Chun-Ju Chiang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
| | - Ya-Wen Yang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
| | - Hung-Chuen Chang
- Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan
| | - San-Lin You
- School of Medicine and Data Science Center, Fu Jen Catholic University, New Taipei City 242008, Taiwan
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12
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Abstract
INTRODUCTION Cholangiocarcinoma is a rare malignancy accounting for 3% of gastrointestinal cancers in the USA. While multiple risk factors for cholangiocarcinoma are established, other potential risk factors are still controversial. Herein, we used a large national database to investigate possible risk factors and associations. METHOD We used the National Inpatient Sample database to review all admissions between 2011 and 2015. We grouped patients based on the presence and absence of cholangiocarcinoma. Using multivariate logistic regression analysis, we assessed the association between obesity, alcohol abuse, smoking, diabetes mellitus and cholangiocarcinoma. RESULTS Out of 30 9552 95 admissions, 20 030 had cholangiocarcinoma. Cholangiocarcinoma patients were older (67 ± 12.8 vs. 57 ± 20.6; P < 0.001) and had fewer female patients (48 vs. 59%; P < 0.001). Multivariate logistic regression analysis showed that diabetes mellitus was associated with cholangiocarcinoma (OR, 1.04; 95% CI, 1.01-1.08; P < 0.001). On the other hand, alcohol, smoking and obesity were all inversely associated with cholangiocarcinoma (OR, 0.75; 95% CI, 0.69-0.81; P < 0.001), (OR, 0.75; 95% CI, 0.71-0.79; P < 0.001) and (OR, 0.71; 95% CI, 0.67-0.75; P < 0.001), respectively. In addition, compared to Whites, Hispanic and Asian/Pacific Islander races were more associated with cholangiocarcinoma (OR, 1.27; 95% CI, 1.21-1.34) and (OR, 1.79; 95% CI, 1.67-1.92) (P < 0.001 for all), respectively, whereas African American race was inversely associated with cholangiocarcinoma (OR, 0.85; 95% CI, 0.81-0.89; P < 0.001). CONCLUSION Patients with a diagnosis of diabetes mellitus or from certain ethnic groups (Hispanic and Asian/Pacific Islander) are associated with increased risk for cholangiocarcinoma.
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13
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Hormati A, Hajrezaei Z, Jazi K, Aslani Kolur Z, Rezvan S, Ahmadpour S. Gastrointestinal and Pancratohepatobiliary Cancers: A Comprehensive Review on Epidemiology and Risk Factors Worldwide. Middle East J Dig Dis 2022; 14:5-23. [PMID: 36619733 PMCID: PMC9489325 DOI: 10.34172/mejdd.2022.251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 11/01/2021] [Indexed: 01/11/2023] Open
Abstract
A significant number of cancer cases are afflicted by gastrointestinal cancers annually. Lifestyle and nutrition have a huge effect on gastrointestinal function, and unhealthy habits have become quite widespread in recent decades, culminating in the rapid growth of gastrointestinal cancers. The most prevalent cancers are lip and mouth cancer, esophageal cancer, gastric cancer, liver and bile duct cancer, pancreatic cancer, and colorectal cancer. Risk factors such as red meat consumption, alcohol consumption, tea, rice, viruses such as Helicobacter pylori and Ebstein Bar Virus (EBV), along with reduced physical activity, predispose the gastrointestinal tract to damage and cause cancer. According to the rapid increase of cancer incidence and late diagnosis of gastrointestinal malignancies, further epidemiological researches remain necessary in order to make appropriate population-based preventive policies. In this study, we reviewed clinical symptoms, risk factors, preventative measures, as well as incidence and mortality rates of gastrointestinal malignancies worldwide with focus on Iranian population.
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Affiliation(s)
- Ahmad Hormati
- Assistant Professor of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Assistant Professor of Gastroenterology and Hepatology, Disease Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Zahra Hajrezaei
- Student Research Committee, Faculty of Medicine, Qom University of Medical Science, Qom, Iran
| | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Qom University of Medical Science, Qom, Iran
| | - Zahra Aslani Kolur
- Student Research Committee, Faculty of Medicine, Qom University of Medical Science, Qom, Iran
| | - Sajjad Rezvan
- Radiology Resident, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Sajjad Ahmadpour
- Gastroenterology and Hepatology Diseases Research Center, Qom University of Medical Sciences, Qom, Iran
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14
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Saldarriaga OA, Dye B, Pham J, Wanninger TG, Millian D, Kueht M, Freiberg B, Utay N, Stevenson HL. Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome. Sci Rep 2021; 11:14506. [PMID: 34267267 PMCID: PMC8282660 DOI: 10.1038/s41598-021-93881-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.
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Affiliation(s)
- Omar A Saldarriaga
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Bradley Dye
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Judy Pham
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Timothy G Wanninger
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Daniel Millian
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Michael Kueht
- Dept. of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Benjamin Freiberg
- Digital Pathology, Araceli Biosciences, 7425 NE Evergreen Pkwy, Hillsboro, OR, 97124, USA
| | - Netanya Utay
- Department of Internal Medicine, University of Texas Health Science Center at Houston, 7000 Fannin St # 1200, Houston, TX, 77030, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA.
- Department of Pathology, The University of Texas Medical Branch, 712 Texas Avenue, Clinical Services Wing-Room 5.506Q, Galveston, TX, 77555-0416, USA.
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15
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Yao WY, Gong W. Immunotherapy in cholangiocarcinoma: From concept to clinical trials. SURGERY IN PRACTICE AND SCIENCE 2021; 5:100028. [DOI: 10.1016/j.sipas.2021.100028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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16
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Du X, Zhang C, Yin C, Wang W, Yan X, Xie D, Zheng X, Zheng Q, Li M, Song Z. High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma. Front Oncol 2021; 11:633899. [PMID: 33828983 PMCID: PMC8019910 DOI: 10.3389/fonc.2021.633899] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 02/09/2021] [Indexed: 12/24/2022] Open
Abstract
Molecular mechanisms underlying the tumorigenesis of a highly malignant cancer, cholangiocarcinoma (CCA), are still obscure. In our study, the CCA expression profile data were acquired from The Cancer Genome Atlas (TCGA) database, and differentially expressed genes (DEGs) in the TCGA-Cholangiocarcinoma (TCGA-CHOL) data set were utilized to construct a co-expression network via weighted gene co-expression network analysis (WGCNA). The blue gene module associated with the histopathologic grade of CCA was screened. Then, five candidate hub genes were screened by combining the co-expression network with protein–protein interaction (PPI) network. After progression and survival analyses, bloom syndrome helicase (BLM) was ultimately identified as a real hub gene. Moreover, the receiver operating characteristic (ROC) curve analysis suggested that BLM had a favorable diagnostic and predictive recurrence value for CCA. The gene set enrichment analysis (GSEA) results for a single hub gene revealed the importance of cell cycle-related pathways in the CCA progression and prognosis. Furthermore, we detected the BLM expression in vitro, and the results demonstrated that the expression level of BLM was much higher in the CCA tissues and cells relative to adjacent non-tumor samples and normal bile duct epithelial cells. Additionally, after further silencing the BLM expression by small interfering RNA (siRNA), the proliferation and migration ability of CCA cells were all inhibited, and the cell cycle was arrested. Altogether, a real hub gene (BLM) and cell cycle-related pathways were identified in the present study, and the gene BLM may be involved in the CCA progression and could act as a reliable biomarker for potential diagnosis and prognostic evaluation.
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Affiliation(s)
- Xiaolong Du
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuanzheng Yin
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjie Wang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xueke Yan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dawei Xie
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xichuan Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qichang Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zifang Song
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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17
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Cancer Vaccines: Antigen Selection Strategy. Vaccines (Basel) 2021; 9:vaccines9020085. [PMID: 33503926 PMCID: PMC7911511 DOI: 10.3390/vaccines9020085] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 02/06/2023] Open
Abstract
Unlike traditional cancer therapies, cancer vaccines (CVs) harness a high specificity of the host’s immunity to kill tumor cells. CVs can train and bolster the patient’s immune system to recognize and eliminate malignant cells by enhancing immune cells’ identification of antigens expressed on cancer cells. Various features of antigens like immunogenicity and avidity influence the efficacy of CVs. Therefore, the choice and application of antigens play a critical role in establishing and developing CVs. Tumor-associated antigens (TAAs), a group of proteins expressed at elevated levels in tumor cells but lower levels in healthy normal cells, have been well-studied and developed in CVs. However, immunological tolerance, HLA restriction, and adverse events are major obstacles that threaten TAA-based CVs’ efficacy due to the “self-protein” characteristic of TAAs. As “abnormal proteins” that are completely absent from normal cells, tumor-specific antigens (TSAs) can trigger a robust immune response against tumor cells with high specificity and without going through central tolerance, contributing to cancer vaccine development feasibility. In this review, we focus on the unique features of TAAs and TSAs and their application in vaccines, summarizing their performance in preclinical and clinical trials.
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18
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Iriana S, Asha K, Repak M, Sharma-Walia N. Hedgehog Signaling: Implications in Cancers and Viral Infections. Int J Mol Sci 2021; 22:1042. [PMID: 33494284 PMCID: PMC7864517 DOI: 10.3390/ijms22031042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
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19
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Zhang Y, Wen Z, Shi X, Liu YJ, Eriksson JE, Jiu Y. The diverse roles and dynamic rearrangement of vimentin during viral infection. J Cell Sci 2020; 134:134/5/jcs250597. [PMID: 33154171 DOI: 10.1242/jcs.250597] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Epidemics caused by viral infections pose a significant global threat. Cytoskeletal vimentin is a major intermediate filament (IF) protein, and is involved in numerous functions, including cell signaling, epithelial-mesenchymal transition, intracellular organization and cell migration. Vimentin has important roles for the life cycle of particular viruses; it can act as a co-receptor to enable effective virus invasion and guide efficient transport of the virus to the replication site. Furthermore, vimentin has been shown to rearrange into cage-like structures that facilitate virus replication, and to recruit viral components to the location of assembly and egress. Surprisingly, vimentin can also inhibit virus entry or egress, as well as participate in host-cell defense. Although vimentin can facilitate viral infection, how this function is regulated is still poorly understood. In particular, information is lacking on its interaction sites, regulation of expression, post-translational modifications and cooperation with other host factors. This Review recapitulates the different functions of vimentin in the virus life cycle and discusses how they influence host-cell tropism, virulence of the pathogens and the consequent pathological outcomes. These insights into vimentin-virus interactions emphasize the importance of cytoskeletal functions in viral cell biology and their potential for the identification of novel antiviral targets.
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Affiliation(s)
- Yue Zhang
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.,University of Chinese Academy of Sciences, Yuquan Road No. 19(A), Shijingshan District, Beijing 100049, China
| | - Zeyu Wen
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.,University of Chinese Academy of Sciences, Yuquan Road No. 19(A), Shijingshan District, Beijing 100049, China
| | - Xuemeng Shi
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yan-Jun Liu
- Shanghai Institute of Cardiovascular Diseases, and Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - John E Eriksson
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku FI-20520, Finland .,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku FI-20520, Finland
| | - Yaming Jiu
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China .,University of Chinese Academy of Sciences, Yuquan Road No. 19(A), Shijingshan District, Beijing 100049, China
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20
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Marônek M, Link R, Monteleone G, Gardlík R, Stolfi C. Viruses in Cancers of the Digestive System: Active Contributors or Idle Bystanders? Int J Mol Sci 2020; 21:ijms21218133. [PMID: 33143318 PMCID: PMC7663754 DOI: 10.3390/ijms21218133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)-composing the gastrointestinal (or digestive) system-contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.
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Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, 040 11 Košice, Slovakia;
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
- Division of Clinical Biochemistry and Clinical Molecular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-06-72596163
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21
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Matsumori T, Kodama Y, Takai A, Shiokawa M, Nishikawa Y, Matsumoto T, Takeda H, Marui S, Okada H, Hirano T, Kuwada T, Sogabe Y, Kakiuchi N, Tomono T, Mima A, Morita T, Ueda T, Tsuda M, Yamauchi Y, Kuriyama K, Sakuma Y, Ota Y, Maruno T, Uza N, Marusawa H, Kageyama R, Chiba T, Seno H. Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma. Cancer Res 2020; 80:5305-5316. [PMID: 33067264 DOI: 10.1158/0008-5472.can-20-1161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/11/2020] [Accepted: 10/13/2020] [Indexed: 11/16/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is frequently driven by aberrant KRAS activation and develops in the liver with chronic inflammation. Although the Notch signaling pathway is critically involved in ICC development, detailed mechanisms of Notch-driven ICC development are still unknown. Here, we use mice whose Notch signaling is genetically engineered to show that the Notch signaling pathway, specifically the Notch/Hes1 axis, plays an essential role in expanding ductular cells in the liver with chronic inflammation or oncogenic Kras activation. Activation of Notch1 enhanced the development of proliferating ductal cells (PDC) in injured livers, while depletion of Hes1 led to suppression. In correlation with PDC expansion, ICC development was also regulated by the Notch/Hes1 axis and suppressed by Hes1 depletion. Lineage-tracing experiments using EpcamcreERT2 mice further confirmed that Hes1 plays a critical role in the induction of PDC and that ICC could originate from PDC. Analysis of human ICC specimens showed PDC in nonneoplastic background tissues, confirming HES1 expression in both PDC and ICC tumor cells. Our findings provide novel direct experimental evidence that Hes1 plays an essential role in the development of ICC via PDC. SIGNIFICANCE: This study contributes to the identification of the cells of origin that initiate ICC and suggests that HES1 may represent a therapeutic target in ICC.
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Affiliation(s)
- Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. .,Department of Gastroenterology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Matsumoto
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Okada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuko Sogabe
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Teruko Tomono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Mima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshihiro Morita
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tatsuki Ueda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Yamauchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yojiro Sakuma
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuji Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Japanese Red Cross Hospital Osaka, Osaka, Japan
| | - Ryoichiro Kageyama
- Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-Ku, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Kansai Electric Power Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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22
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Sepulveda-Crespo D, Resino S, Martinez I. Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants. Vaccines (Basel) 2020; 8:vaccines8020313. [PMID: 32560440 PMCID: PMC7350220 DOI: 10.3390/vaccines8020313] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023] Open
Abstract
Despite successful treatments, hepatitis C virus (HCV) infections continue to be a significant world health problem. High treatment costs, the high number of undiagnosed individuals, and the difficulty to access to treatment, particularly in marginalized susceptible populations, make it improbable to achieve the global control of the virus in the absence of an effective preventive vaccine. Current vaccine development is mostly focused on weakly immunogenic subunits, such as surface glycoproteins or non-structural proteins, in the case of HCV. Adjuvants are critical components of vaccine formulations that increase immunogenic performance. As we learn more information about how adjuvants work, it is becoming clear that proper stimulation of innate immunity is crucial to achieving a successful immunization. Several hepatic cell types participate in the early innate immune response and the subsequent inflammation and activation of the adaptive response, principally hepatocytes, and antigen-presenting cells (Kupffer cells, and dendritic cells). Innate pattern recognition receptors on these cells, mainly toll-like receptors, are targets for new promising adjuvants. Moreover, complex adjuvants that stimulate different components of the innate immunity are showing encouraging results and are being incorporated in current vaccines. Recent studies on HCV-vaccine adjuvants have shown that the induction of a strong T- and B-cell immune response might be enhanced by choosing the right adjuvant.
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Affiliation(s)
| | - Salvador Resino
- Correspondence: (S.R.); (I.M.); Tel.: +34-91-8223266 (S.R.); +34-91-8223272 (I.M.); Fax: +34-91-5097919 (S.R. & I.M.)
| | - Isidoro Martinez
- Correspondence: (S.R.); (I.M.); Tel.: +34-91-8223266 (S.R.); +34-91-8223272 (I.M.); Fax: +34-91-5097919 (S.R. & I.M.)
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