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Liang C, Kan J, Wang J, Lu W, Mo X, Zhang B. Nasopharyngeal carcinoma-associated inflammatory cytokines: ongoing biomarkers. Front Immunol 2024; 15:1448012. [PMID: 39483474 PMCID: PMC11524805 DOI: 10.3389/fimmu.2024.1448012] [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: 06/12/2024] [Accepted: 10/02/2024] [Indexed: 11/03/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a neoplasm related to inflammation; the expression of cytokines, such as CCL3, CCL4, CCL20, IL-1α, IL-1β, IL-6, IL-8, and IL-10, among others, is presumed to be associated with NPC occurrence and development. Therefore, the circulating levels of these cytokines may be potential biomarkers for assessing tumor aggressiveness, exploring cellular interactions, and monitoring tumor therapeutic responses. Numerous scholars have comprehensively explored the putative mechanisms through which these inflammatory factors affect NPC progression and therapeutic responses. Moreover, investigations have focused on elucidating the correlation between the systemic levels of these cytokines and the incidence and prognosis of NPC. This comprehensive review aims to delineate the advancements in research concerning the relationship between inflammatory factors and NPC while considering their prospective roles as novel prognostic and predictive biomarkers in the context of NPC.
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Affiliation(s)
- Chuwen Liang
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun Kan
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jingli Wang
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wei Lu
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaoyan Mo
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bei Zhang
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Allen DZ, Aljabban J, Silverman D, McDermott S, Wanner RA, Rohr M, Hadley D, Panahiazar M. Meta-Analysis illustrates possible role of lipopolysaccharide (LPS)-induced tissue injury in nasopharyngeal carcinoma (NPC) pathogenesis. PLoS One 2021; 16:e0258187. [PMID: 34648530 PMCID: PMC8516236 DOI: 10.1371/journal.pone.0258187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 09/21/2021] [Indexed: 12/20/2022] Open
Abstract
Background Nasopharyngeal carcinoma (NPC) is a cancer of epithelial origin with a high incidence in certain populations. While NPC has a high remission rate with concomitant chemoradiation, recurrences are frequent, and the downstream morbidity of treatment is significant. Thus, it is imperative to find alternative therapies. Methods We employed a Search Tag Analyze Resource (STARGEO) platform to conduct a meta-analysis using the National Center for Biotechnology’s (NCBI) Gene Expression Omnibus (GEO) to define NPC pathogenesis. We identified 111 tumor samples and 43 healthy nasopharyngeal epithelium samples from NPC public patient data. We analyzed associated signatures in Ingenuity Pathway Analysis (IPA), restricting genes that showed statistical significance (p<0.05) and an absolute experimental log ratio greater than 0.15 between disease and control samples. Results Our meta-analysis identified activation of lipopolysaccharide (LPS)-induced tissue injury in NPC tissue. Additionally, interleukin-1 (IL-1) and SB203580 were the top upstream regulators. Tumorigenesis-related genes such as homeobox A10 (HOXA10) and prostaglandin-endoperoxide synthase 2 (PTGS2 or COX-2) as well as those associated with extracellular matrix degradation, such as matrix metalloproteinases 1 and 3 (MMP-1, MMP-3) were also upregulated. Decreased expression of genes that encode proteins associated with maintaining healthy nasal respiratory epithelium structural integrity, including sentan-cilia apical structure protein (SNTN) and lactotransferrin (LTF) was documented. Importantly, we found that etanercept inhibits targets upregulated in NPC and LPS induction, such as MMP-1, PTGS2, and possibly MMP-3. Conclusions Our analysis illustrates that nasal epithelial barrier dysregulation and maladaptive immune responses are key components of NPC pathogenesis along with LPS-induced tissue damage.
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Affiliation(s)
- David Z. Allen
- The Ohio State College of Medicine, Columbus, Ohio, United States of America
- * E-mail:
| | - Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, United States of America
| | - Dustin Silverman
- Department of Otolaryngology, The Ohio State Wexner Medical Center, Columbus, Ohio, United States of America
| | - Sean McDermott
- The Ohio State College of Medicine, Columbus, Ohio, United States of America
| | - Ross A. Wanner
- The Ohio State College of Medicine, Columbus, Ohio, United States of America
| | - Michael Rohr
- University of Central Florida, Orlando, Florida, United States of America
| | - Dexter Hadley
- Department of Pathology, University of Central Florida, Orlando, Florida, United States of America
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, California, United States of America
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Sahinli H, Akyürek N, Yılmaz M, Kandemir O, Duran AO, Kulaçoğlu S, Uçar G, Acar E, Özet A, Gümüş M, Ç Öksüzoğlu ÖB, Özdemir NY. PD-L1 expression in immune cells is a favorable prognostic factor for nasopharyngeal carcinoma. Indian J Cancer 2020; 58:561-566. [PMID: 33402600 DOI: 10.4103/ijc.ijc_459_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Programmed death-ligand 1 (PD-L1) has been determined as a reliable prognostic factor for various malignancies. In this study, we aimed to determine the prognostic effect of PD-L1 expression in tumor-infiltrating immune cells (TIICs) of nasopharyngeal carcinoma (NPC) patients. Methods Seventy patients diagnosed with non-metastatic NPC were included in the study. PD-L1 expression on immune cells was analyzed by immunohistochemical method. Patients were categorized into two groups according to the PD-L1 expression level in TIICs (level of PD-L1 staining ≥5% positive vs <5% negative). Results Median follow-up period was 34 months (range = 1 - 188). 1 and 2 years survival rate were found as 75% and 63% in PD-L1 negative TIICs group (47%), and 85% and 83% in PD-L1 positive TIICs group (53%), respectively. PD-L1 positivity in immune cells (ICs) was detected in 53% of the patients. The survival rate was found better in the PD- L1 positive group compared to the negative group (P = 0.049). Discussion In conclusion, the survival rate was found significantly better in the PD-L1 positive TIICs group, compared to the negative group.
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Affiliation(s)
- Hayriye Sahinli
- Department of Oncology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Nalan Akyürek
- Department of Pathology, Gazi University Medical Hospital, Ankara, Turkey
| | - Mukaddes Yılmaz
- Department of Oncology, Gazi University Medical University Hospital, Ankara, Turkey
| | - Olcay Kandemir
- Department of Pathology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
| | - Ayşe Ocak Duran
- Department of Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
| | - Sezer Kulaçoğlu
- Department of Pathology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Gökhan Uçar
- Department of Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Elif Acar
- Department of Pathology, Gazi University Medical Hospital, Ankara, Turkey
| | - Ahmet Özet
- Department of Oncology, Gazi University Medical University Hospital, Ankara, Turkey
| | - Mahmut Gümüş
- Department of Oncology, Medical School of Istanbul Medipol University, Istanbul, Turkey
| | - Ö Berna Ç Öksüzoğlu
- Department of Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
| | - Nuriye Y Özdemir
- Department of Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
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Novel Therapies Boosting T Cell Immunity in Epstein Barr Virus-Associated Nasopharyngeal Carcinoma. Int J Mol Sci 2020; 21:ijms21124292. [PMID: 32560253 PMCID: PMC7352617 DOI: 10.3390/ijms21124292] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/05/2020] [Accepted: 06/12/2020] [Indexed: 12/11/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumour of the head and neck affecting localised regions of the world, with the highest rates described in Southeast Asia, Northern Africa, and Greenland. Its high morbidity rate is linked to both late-stage diagnosis and unresponsiveness to conventional anti-cancer treatments. Multiple aetiological factors have been described including environmental factors, genetics, and viral factors (Epstein Barr Virus, EBV), making NPC treatment that much more complex. The most common forms of NPCs are those that originate from the epithelial tissue lining the nasopharynx and are often linked to EBV infection. Indeed, they represent 75–95% of NPCs in the low-risk populations and almost 100% of NPCs in high-risk populations. Although conventional surgery has been improved with nasopharyngectomy’s being carried out using more sophisticated surgical equipment for better tumour resection, recent findings in the tumour microenvironment have led to novel treatment options including immunotherapies and photodynamic therapy, able to target the tumour and improve the immune system. This review provides an update on the disease’s aetiology and the future of NPC treatments with a focus on therapies activating T cell immunity.
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Tsang C, Lo K, Nicholls JM, Huang S, Tsao S. Pathogenesis of Nasopharyngeal Carcinoma. NASOPHARYNGEAL CARCINOMA 2019:45-64. [DOI: 10.1016/b978-0-12-814936-2.00003-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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da Costa VG, Marques-Silva AC, Moreli ML. The Epstein-Barr virus latent membrane protein-1 (LMP1) 30-bp deletion and XhoI-polymorphism in nasopharyngeal carcinoma: a meta-analysis of observational studies. Syst Rev 2015; 4:46. [PMID: 25927427 PMCID: PMC4404015 DOI: 10.1186/s13643-015-0037-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/26/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV) is considered to be closely associated with nasopharyngeal carcinoma (NPC), in which EBV-encoded latent membrane protein 1 (LMP1) was found to have an oncogenic role. However, the results published on the LMP1 polymorphism are inconsistent. In the present study, we performed a meta-analysis to determine the frequency of the associations and a more precise association between NPC and EBV LMP1 gene variants (30-bp deletion (del)/XhoI-loss). METHODS Eligible articles met the inclusion/exclusion criteria and were identified in the following electronic databases: PubMed, ScienceDirect, and SciELO. Consequently, the data of interest were extracted and plotted in a table to calculate the frequency and odds ratio (OR) of the outcomes of interest (30-bp del-LMP1/XhoI-loss) in patients with NPC. Study quality (Newcastle-Ottawa Scale (NOS)), publication bias, and heterogeneity were assessed. RESULTS Thirty-one observational studies were included with a total of 2,846 individuals (NPC, n = 1,855; control, n = 991). The risk of bias in relation to study quality evaluated by NOS was considered low. The pooled estimate of the frequency of 30-bp del-LMP1 and XhoI-loss in patients with NPC was 77% (95% confidence interval (CI): 72 to 82) and 82% (95% CI: 71 to 92), respectively. There was an association between 30-bp del-LMP1 and NPC susceptibility (OR = 2.86, 95% CI: 1.35 to 6.07, P = 0.00). Similarly, there was an association between XhoI-loss and NPC (OR = 8.5, 95% CI: 1.7 to 41, P = 0.00). However, when we analyze the co-existence of the 30-bp del-LMP1 and XhoI-loss in patients with NPC, there was no association (OR = 1.09, 95% CI: 0.06 to 18.79, P = 0.002). CONCLUSIONS Our results suggest an association between the 30-bp del-LMP1 and XhoI-loss with NPC susceptibility. However, our data should be interpreted with caution because the sample size was small, and there was heterogeneity between the studies. Thus, future studies are needed with adjusted estimates to simultaneously evaluate multiple factors involved in the development of NPC. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42014013496 .
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Affiliation(s)
- Vivaldo G da Costa
- Post-Graduation Program in Applied Health Sciences, Federal University of Goiás, BR 364, Km 192, Industrial Park, Jataí, Brazil.
- Virology Laboratory, Federal University of Goiás, BR 364, Km 192, Industrial Park, Jataí, Brazil.
| | - Ariany C Marques-Silva
- Virology Laboratory, Federal University of Goiás, BR 364, Km 192, Industrial Park, Jataí, Brazil.
| | - Marcos L Moreli
- Post-Graduation Program in Applied Health Sciences, Federal University of Goiás, BR 364, Km 192, Industrial Park, Jataí, Brazil.
- Virology Laboratory, Federal University of Goiás, BR 364, Km 192, Industrial Park, Jataí, Brazil.
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Solinas A, Calvisi DF. Lessons from rare tumors: Hepatic lymphoepithelioma-like carcinomas. World J Gastroenterol 2015; 21:3472-3479. [PMID: 25834311 PMCID: PMC4375568 DOI: 10.3748/wjg.v21.i12.3472] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 12/11/2014] [Accepted: 02/05/2015] [Indexed: 02/06/2023] Open
Abstract
In this review we focus on lymphoepithelioma-like hepatocellular carcinomas (LEL-HCC) and lymphoepithelioma-like cholangiocarcinomas (LEL-ICC). Despite their rarity, these tumors are of general interest because of their epidemiological and clinical features, and because they represent a distinct model of interaction between the immune system and neoplastic cells. Approximately half of LEL-HCC arise in the context of chronic hepatitis C virus (HCV) infection and have been described both in Eastern and Western patients. By contrast, LEL-ICC is associated in almost all cases with Epstein-Barr virus (EBV) infection and exhibits the same epidemiological features of EBV related malignancies. Compared with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma of corresponding stage, both LEL-HCC and LEL-ICC are characterized by lower rates of recurrence after surgery and better overall survival. How this behavior is related to distinct genetic alterations and tumor microenvironment is unclear. The pathophysiological mechanisms of lymphoid infiltrations seem to be different among the two groups of tumors. In fact, LEL-HCC frequently arises in the context of inflammatory changes driven by HCV infection, and has been recognized as a variant of classical hepatocellular carcinoma. At variance, lymphocyte recruitment of LEL-ICC is similar to that described in nasopharyngeal carcinoma and gastric LEL, and possibly depends on the expression pattern of latent EBV infection.
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Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T, Guigay J, Pancré V, de Launoit Y, Busson P, Moralès O, Delhem N. Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. J Natl Cancer Inst 2014; 107:363. [PMID: 25505237 DOI: 10.1093/jnci/dju363] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC). METHODS Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided. RESULTS CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4(+)CD25(-) T cells and mediated their conversion into inhibitory CD4(+)CD25(high) cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3(Low) Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75 (P < .001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1). CONCLUSION Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.
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Affiliation(s)
- Dhafer Mrizak
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Nathalie Martin
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Clément Barjon
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Anne-Sophie Jimenez-Pailhes
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Rami Mustapha
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Toshiro Niki
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Joël Guigay
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Véronique Pancré
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Yvan de Launoit
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Pierre Busson
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Olivier Moralès
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG).
| | - Nadira Delhem
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG).
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Control of the inflammatory response mechanisms mediated by natural and induced regulatory T-cells in HCV-, HTLV-1-, and EBV-associated cancers. Mediators Inflamm 2014; 2014:564296. [PMID: 25525301 PMCID: PMC4267219 DOI: 10.1155/2014/564296] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 06/18/2014] [Accepted: 07/30/2014] [Indexed: 02/07/2023] Open
Abstract
Virus infections are involved in chronic inflammation and, in some cases, cancer development. Although a viral infection activates the immune system's response that eradicates the pathogen mainly through inflammatory mechanisms, it is now recognized that this inflammatory condition is also favorable to the development of tumors. Indeed, it is well described that viruses, such as hepatitis C virus (HCV), Epstein Barr virus (EBV), human papillomavirus (HPV) or human T-cell lymphotropic virus type-1 (HTLV-1), are important risk factors for tumor malignancies. The inflammatory response is a fundamental immune mechanism which involves several molecular and cellular components consisting of cytokines and chemokines that are released by various proinflammatory cells. In parallel to this process, some endogenous recruited components release anti-inflammatory mediators to restore homeostasis. The development of tools and strategies using viruses to hijack the immune response is mostly linked to the presence of regulatory T-cells (Treg) that can inhibit inflammation and antiviral responses of other effector cells. In this review, we will focus on current understanding of the role of natural and induced Treg in the control and the resolution of inflammatory response in HCV-, HTLV-1-, and EBV-associated cancers.
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10
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Rickinson AB. Co-infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 2014; 26:99-115. [PMID: 24751797 DOI: 10.1016/j.semcancer.2014.04.004] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 04/04/2014] [Indexed: 12/24/2022]
Abstract
Epstein-Barr virus (EBV) is aetiologically linked to a wide range of human tumours. Some arise as accidents of the virus' lifestyle in its natural niche, the B lymphoid system; these include B-lymphoproliferative disease of the immunocompromised, Hodgkin Lymphoma, Burkitt Lymphoma and particular forms of diffuse large B cell lymphoma. Interestingly, HIV infection increases the incidence of each of these B cell malignancies, though by different degrees and for different reasons. Other EBV-associated tumours arise through rare viral entry into unnatural target tissues; these include all cases of nasal T/NK cell lymphoma and of undifferentiated nasopharyngeal carcinoma plus a small but significant subset of gastric carcinomas, a tumour type more generally associated with chronic Helicobacter pylori infection. Understanding EBV's involvement in the pathogenesis of these different malignancies is an important long-term goal. This article focuses on two overlapping, but relatively neglected, areas of research that could contribute to that goal. The first addresses the mechanisms whereby coincident infections with other pathogens increase the risk of EBV-positive malignancies, and takes as its paradigm the actions of holoendemic malaria and HIV infections as co-factors in Burkitt lymphomagenesis. The second widens the argument to include both infectious and non-infectious sources of chronic inflammation in the pathogenesis of EBV-positive tumours such as T/NK cell lymphoma, nasopharyngeal carcinoma and gastric carcinoma.
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Affiliation(s)
- A B Rickinson
- School of Cancer Sciences, University of Birmingham, Birmingham, UK.
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11
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Gourzones C, Klibi-Benlagha J, Friboulet L, Jlidi R, Busson P. Cellular Interactions in Nasopharyngeal Carcinomas. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013. [DOI: 10.1007/978-1-4614-5947-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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12
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Gourzones C, Barjon C, Busson P. Host-tumor interactions in nasopharyngeal carcinomas. Semin Cancer Biol 2012; 22:127-36. [PMID: 22249142 DOI: 10.1016/j.semcancer.2012.01.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 12/29/2011] [Accepted: 01/03/2012] [Indexed: 12/13/2022]
Abstract
Like other human solid tumors, nasopharyngeal carcinoma (NPC) is a tissue and a systemic disease as much as a cell disease. Tumor cell population in NPC is highly heterogeneous. Heavy infiltration by non-malignant leucocytes results at least in part from the production of abundant inflammatory cytokines by the malignant epithelial cells. There is indirect evidence that interactions between stromal and malignant cells contribute to tumor development. Peripheral blood samples collected from NPC patients contain multiple products derived from the tumor, including cytokines, non-cytokine tumor proteins, tumor exosomes and viral nucleic acids. These products represent a potential source of biomarkers for assessment of tumor aggressiveness, indirect exploration of cellular interactions and monitoring of tumor response to therapeutic agents. Most NPC patients are immunocompetent with evidence of active humoral and cellular immune responses against EBV-antigens at the systemic level. Tumor development is facilitated by local immunosuppressive factors which are not fully understood. Local accumulation of regulatory T-cells is probably one important factor. At least two NPC tumor products are suspected to contribute to their expansion, the cytokine CCL20 and the tumor exosomes carrying galectin 9. In the future, new therapeutic modalities will probably aim at breaking immune tolerance or at blocking cellular interactions critical for tumor growth.
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Affiliation(s)
- Claire Gourzones
- Université Paris-Sud-11, CNRS-UMR 8126 and Institut de cancérologie Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France
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Yang ZH, Dai Q, Zhong L, Zhang X, Guo QX, Li SN. Association of IL-1 polymorphisms and IL-1 serum levels with susceptibility to nasopharyngeal carcinoma. Mol Carcinog 2011; 50:208-214. [PMID: 21154765 DOI: 10.1002/mc.20706] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Revised: 10/02/2010] [Accepted: 10/19/2010] [Indexed: 12/11/2022]
Abstract
Previous studies demonstrated that the polymorphism of interleukin-1 (IL-1) produce alterations of the protein expression and may contribute to oncogenetic processes. The aim of this study was to investigate the relationship between IL-1A gene polymorphisms and NPC susceptibility and the influence of on IL-1α serum levels in cases versus controls. To test whether the genetic variants of IL-1A gene modify the risk of nasopharyngeal carcinoma (NPC), we compared the -889C/T and rs3783553 polymorphisms between 248 patients with NPC and 296 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. Serum IL-1α levels were measured by enzyme-linked immunosorbent assay. The rs3783553 (TTCA insertion or deletion) polymorphism of the IL-1A gene was significantly associated with the susceptibility to NPC. The variant homozygote genotype +/+ was associated with a significantly reduced risk of NPC as compared with the wild homozygote -/- genotype, and the serum IL-1α levels were significantly lower in individuals with homozygous +/+ genotypes. No association was found between the -889C/T polymorphisms and risk of NPC, and no statistically significant differences were found between rs3783553 polymorphism and clinical pathology indices. The IL-1A rs3783553 polymorphism might contribute to a risk of developing NPC by affecting the serum IL-1α secretion in the Chinese population.
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Affiliation(s)
- Zhi-Hui Yang
- Department of Pathology, Luzhou Medical College, Luzhou, Sichuan, People's Republic of China
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14
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Koon HK, Lo KW, Leung KN, Lung ML, Chang CCK, Wong RNS, Leung WN, Mak NK. Photodynamic therapy-mediated modulation of inflammatory cytokine production by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Cell Mol Immunol 2010; 7:323-6. [PMID: 20228836 PMCID: PMC4003233 DOI: 10.1038/cmi.2010.4] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Revised: 01/08/2010] [Accepted: 01/19/2010] [Indexed: 12/18/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant disease associated with Epstein-Barr virus (EBV) infection. This study aims to examine the effects of EBV infection on the production of proinflammatory cytokines in NPC cells after the Zn-BC-AM photodynamic therapy (PDT) treatment. Cells were treated with the photosensitiser Zn-BC-AM for 24 h before light irradiation. Quantitative ELISA was used to evaluate the production of cytokines. Under the same experimental condition, HK-1-EBV cells produced a higher basal level of IL-1alpha (1561 pg/ml), IL-1beta (16.6 pg/ml) and IL-8 (422.9 pg/ml) than the HK-1 cells. At the light dose of 0.25-0.5 J/cm(2), Zn-BC-AM PDT-treated HK-1-EBV cells were found to produce a higher level of IL-1alpha and IL-1beta than the HK-1 cells. The production of IL-1beta appeared to be mediated via the IL-1beta-converting enzyme (ICE)-independent pathway. In contrast, the production of angiogenic IL-8 was downregulated in both HK-1 and HK-1-EBV cells after Zn-BC-AM PDT. Our results suggest that Zn-BC-AM PDT might indirectly reduce tumour growth through the modulation of cytokine production.
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Affiliation(s)
- Ho-Kee Koon
- Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong
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15
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Hui ABY, Yue S, Shi W, Alajez NM, Ito E, Green SR, Frame S, O'Sullivan B, Liu FF. Therapeutic efficacy of seliciclib in combination with ionizing radiation for human nasopharyngeal carcinoma. Clin Cancer Res 2009; 15:3716-24. [PMID: 19470731 DOI: 10.1158/1078-0432.ccr-08-2790] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Seliciclib is a small-molecule cyclin-dependent kinase inhibitor, which has been reported to induce apoptosis and cell cycle arrest in EBV-negative nasopharyngeal carcinoma cell lines. Because most nasopharyngeal carcinoma patients harbor EBV, we proceeded to evaluate the cytotoxic effects of seliciclib in EBV-positive nasopharyngeal carcinoma models. EXPERIMENTAL DESIGN Cytotoxicity of seliciclib was investigated in the EBV-positive cell line C666-1 and the C666-1 and C15 xenograft models. Caspase activities and cell cycle analyses were measured by flow cytometry. Efficacy of combined treatment of seliciclib with radiation therapy was also evaluated. RESULTS Seliciclib caused significant cytotoxicity in the C666-1 cells in a time- and dose-dependent manner, with accumulation of cells in both sub-G(1) and G(2)-M phases, indicative of apoptosis and cell cycle arrest, respectively. Caspase-2, -3, -8, and -9 activities were all increased, with caspase-3 being the most significantly activated at 48 h after treatment. These cells also showed a reduction of Mcl-1 mRNA and protein levels. Combined treatment of seliciclib with radiation therapy showed a synergistic interaction with enhanced cytotoxicity in C666-1 cells and delayed repair of double-strand DNA breaks. For in vivo models, significant delays in tumor growth were observed for both C666-1 and C15 tumors, which were associated with enhanced apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry analyses. CONCLUSIONS Seliciclib enhanced the antitumor efficacy of radiation therapy in EBV-positive nasopharyngeal carcinoma, characterized by G(2)-M arrest, and apoptosis, associated with an induction in caspase activity. This process is mediated by reduction in Mcl-1 expression and by attenuation of double-strand DNA break repair.
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Affiliation(s)
- Angela B Y Hui
- Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, University of Toronto, Canada
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16
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Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood 2008; 113:1957-66. [PMID: 19005181 DOI: 10.1182/blood-2008-02-142596] [Citation(s) in RCA: 340] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes. Here, we sought to determine whether galectin-9-carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9-containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3-binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBV-specific CD4(+) cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC.
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Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer 2006; 6:283. [PMID: 17156439 PMCID: PMC1779799 DOI: 10.1186/1471-2407-6-283] [Citation(s) in RCA: 206] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2006] [Accepted: 12/08/2006] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Nasopharyngeal carcinomas (NPC) are consistently associated with the Epstein-Barr virus (EBV). Their malignant epithelial cells contain the viral genome and express several antigenic viral proteins. However, the mechanisms of immune escape in NPCs are still poorly understood. EBV-transformed B-cells have been reported to release exosomes carrying the EBV-encoded latent membrane protein 1 (LMP1) which has T-cell inhibitory activity. Although this report suggested that NPC cells could also produce exosomes carrying immunosuppressive proteins, this hypothesis has remained so far untested. METHODS Malignant epithelial cells derived from NPC xenografts--LMP1-positive (C15) or negative (C17)--were used to prepare conditioned culture medium. Various microparticles and vesicles released in the culture medium were collected and fractionated by differential centrifugation. Exosomes collected in the last centrifugation step were further purified by immunomagnetic capture on beads carrying antibody directed to HLA class II molecules. Purified exosomes were visualized by electron microscopy and analysed by western blotting. The T-cell inhibitory activities of recombinant LMP1 and galectin 9 were assessed on peripheral blood mononuclear cells activated by CD3/CD28 cross-linking. RESULTS HLA-class II-positive exosomes purified from C15 and C17 cell supernatants were containing either LMP1 and galectin 9 (C15) or galectin 9 only (C17). Recombinant LMP1 induced a strong inhibition of T-cell proliferation (IC50 = 0.17 nM). In contrast recombinant galectin 9 had a weaker inhibitory effect (IC50 = 46 nM) with no synergy with LMP1. CONCLUSION This study provides the proof of concept that NPC cells can release HLA class-II positive exosomes containing galectin 9 and/or LMP1. It confirms that the LMP1 molecule has intrinsic T-cell inhibitory activity. These findings will encourage investigations of tumor exosomes in the blood of NPC patients and assessment of their effects on various types of target cells.
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18
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Teichmann M, Meyer B, Beck A, Niedobitek G. Expression of the interferon-inducible chemokine IP-10 (CXCL10), a chemokine with proposed anti-neoplastic functions, in Hodgkin lymphoma and nasopharyngeal carcinoma. J Pathol 2005; 206:68-75. [PMID: 15751051 DOI: 10.1002/path.1745] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) are characterized by their association with Epstein-Barr virus (EBV) and an abundant infiltrate of reactive lymphoid cells. The presence of this lymphoid stroma may influence the effect of anti-viral immunotherapy. The interferon-inducible chemokine IP-10 has anti-neoplastic effects in several model systems mediated by T-cells expressing the CXCR3 chemokine receptor. Using in situ hybridization, it is shown that IP-10 is expressed in neoplastic cells of HL and correlates both with the mixed cellularity histotype and with EBV infection. IP-10 expression was also detected in tumour cells of most NPCs as well as in EBV-negative squamous cell carcinomas of the tongue. Thus, in carcinomas, IP-10 expression showed no correlation with EBV infection. Numerous CXCR3-positive lymphocytes were detected in the lymphoid stroma of HL and NPC, raising the possibility of a Th1-predominant immune response in these cases. In view of the proposed anti-neoplastic functions of IP-10 and CXCR3-positive lymphocytes, these findings are unexpected and raise the possibility that endogenous IP-10 expression in the context of human tumours may not exert the anti-tumour effects ascribed to it by in vitro experiments.
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MESH Headings
- Animals
- Carcinoma/immunology
- Carcinoma/virology
- Carcinoma, Squamous Cell/immunology
- Case-Control Studies
- Cell Line, Tumor
- Chemokine CXCL10
- Chemokines, CXC/analysis
- Chemokines, CXC/immunology
- Colonic Neoplasms/immunology
- Epstein-Barr Virus Infections/immunology
- Herpesvirus 4, Human
- Hodgkin Disease/immunology
- Hodgkin Disease/virology
- Humans
- Immunohistochemistry/methods
- In Situ Hybridization
- Mice
- Mice, Nude
- Nasopharyngeal Neoplasms/immunology
- Nasopharyngeal Neoplasms/virology
- Neoplasms, Experimental
- RNA, Messenger/analysis
- Receptors, CXCR3
- Receptors, Chemokine/analysis
- Receptors, Chemokine/genetics
- Tongue Neoplasms/immunology
- Viral Matrix Proteins/analysis
- Viral Matrix Proteins/genetics
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Affiliation(s)
- Martina Teichmann
- Institute for Pathology, Friedrich-Alexander-University, Erlangen, Germany
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19
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Hu H, Tang KF, Chua YN, Lu J, Feng P, Chew CT, Chan SH. Expression of interleukin-18 by nasopharyngeal carcinoma cells: a factor that possibly initiates the massive leukocyte infiltration. Hum Pathol 2004; 35:722-8. [PMID: 15188138 DOI: 10.1016/j.humpath.2004.01.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Interleukin-18 (IL-18) is a single-chain cytokine that is produced by various cells. With interleukin-12 (IL-12), it synergistically stimulates activated T cells and natural killer (NK) cells to produce interferon-gamma (IFN-gamma). Nasopharyngeal carcinoma (NPC) is the most common form of nasal and nasopharyngeal malignancy, and in NPC tumor tissues there is an intense leukocyte infiltration comprising predominantly T cells and macrophages. We previously showed an increased expression of IFN-gamma in the infiltrating T cells. To identify the cells that provide IL-12 and IL-18 for stimulating the expression of IFN-gamma in activated T cells, NPC cell lines CNE-2 and HK-1, as well as biopsies obtained from NPC and control individuals, were examined. CNE-2 and HK-1 cells were found to express messenger RNA encoding IL-18, but not IL-12. Secreted IL-18 was detected in the culture supernatant. Addition of a caspase-1 inhibitor decreased the secretion level, indicating that this IL-18 secretion was caspase-1 dependent. Moreover, the in vitro IL-18 production in NPC cell lines correlated with the NPC tumor cells in situ. NPC tumor cells in the biopsies produced IL-18, as detected by immunohistochemistry and immunofluorescent double staining. In contrast, IL-18 expression was not observed in the control biopsies. We suggest that IL-18 secreted by NPC tumor cells plays a role in initiating the leukocyte infiltration process. IL-18 stimulates T cells and NK cells to produce IFN-gamma, which consequently activates macrophages and other immune cells to secrete chemokines to start a leukocyte recruitment cascade.
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Affiliation(s)
- Huaizhong Hu
- Department of Microbiology, Faculty of Medicine, National University Medical Institute, National University of Singapore, Singapore, Singapore
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20
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Chong JM, Sakuma K, Sudo M, Osawa T, Ohara E, Uozaki H, Shibahara J, Kuroiwa K, Tominaga SI, Hippo Y, Aburatani H, Funata N, Fukayama M. Interleukin-1beta expression in human gastric carcinoma with Epstein-Barr virus infection. J Virol 2002; 76:6825-31. [PMID: 12050395 PMCID: PMC136266 DOI: 10.1128/jvi.76.13.6825-6831.2002] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The KT tumor is a transplantable strain of a human Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), established in severe combined immunodeficiency (SCID) mice, with which the cytokine expression of EBVaGC can be investigated without interference from the infiltrating lymphocytes. As a part of a high-density oligonucleotide array (GeneChip) analysis of EBVaGC, the interleukin-1beta (IL-1beta) gene was the only cytokine gene that showed markedly higher expression in the KT tumor cells than in two tumor strains of EBV-negative GC. The results were confirmed by Northern blotting, Western blotting, and enzyme-linked immunosorbent assay. Furthermore, we demonstrated a positive signal for IL-1beta mRNA in the carcinoma cells of a surgically resected EBVaGC, but not in EBV-negative GC, by in situ hybridization. In vitro, IL-1beta increased the cell growth of a GC cell line, TMK1. Thus, IL-1beta may act as an autocrine growth factor in EBVaGC.
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Affiliation(s)
- Ja-Mun Chong
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
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21
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La biologie des carcinomes nasopharyngés en 2001: mise à jour et perspectives. Cancer Radiother 2001. [DOI: 10.1016/s1278-3218(01)80027-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Niedobitek G, Meru N, Delecluse HJ. Epstein-Barr virus infection and human malignancies. Int J Exp Pathol 2001. [PMID: 11488990 DOI: 10.1111/j.1365-2613.2001.iep190.x] [Citation(s) in RCA: 129] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The Epstein-Barr virus (EBV) is a herpes virus which establishes a life-long persistent infection in over 90% of the human adult population world-wide. Based on its association with a variety of lymphoid and epithelial malignancies, EBV has been classified as a group 1 carcinogen by the International Agency for Research on Cancer. In this article we discuss the evidence supporting an aetiological role for EBV in the pathogenesis of human tumours. The biology of EBV infection will be described with special emphasis on viral transforming gene products. A brief survey of EBV-associated tumours is followed by a discussion of specific problems. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated tumours also in patients without clinically manifest immunodeficiencies. Finally, the timing of EBV infection in the pathogenesis of virus-associated malignancies is discussed. There is good evidence that EBV infection precedes expansion of the malignant cell populations in some virus-associated tumours. However, this is clearly not always the case and for some of these tumours there are indications that clonal genetic alterations may occur prior to EBV infection. Thus, whilst there is good evidence to suggest that EBV is a human carcinogen, its precise role(s) in the development of virus-associated human tumours requires clarification.
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Affiliation(s)
- G Niedobitek
- Pathologisches Institut, Friedrich-Alexander-Universität, Krankenhausstr. 8-10, 91054 Erlangen, Germany. gerald.niedobitek @patho.imed.uni-erlangen.de
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23
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Beck A, Päzolt D, Grabenbauer GG, Nicholls JM, Herbst H, Young LS, Niedobitek G. Expression of cytokine and chemokine genes in Epstein-Barr virus-associated nasopharyngeal carcinoma: comparison with Hodgkin's disease. J Pathol 2001; 194:145-51. [PMID: 11400141 DOI: 10.1002/path.867] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Nasopharyngeal carcinoma (NPC) and Hodgkin's disease (HD) are characterized by their association with Epstein-Barr virus (EBV) and the presence of an intense lymphoid stroma, consisting of T lymphocytes and other reactive cells. In both entities, the tumour cells express viral proteins known to provide target epitopes for cytotoxic T-cells (CTLs), yet in vivo, the tumour cells appear to escape CTL recognition. A comparative in situ hybridization study of cytokine and chemokine gene expression in NPC and HD has been undertaken, focusing on cytokines which are known to be inducible by EBV in vitro. Hodgkin and Reed-Sternberg (HRS) cells expressed interleukin (IL)-6, IL-8, and IL-10, and the thymus and activation regulated chemokine (TARC) in 15/22, 0/22, 5/22, and 16/21 cases, respectively. In NPC, the epithelial tumour cells showed expression of IL-6 in 3/43 cases and of IL-8 in 2/40 cases. There was no detectable expression of IL-10 and TARC in these cases. These data confirm that HRS cells frequently express cytokine and chemokine genes and suggest that this may enable HRS cells to modulate the immune response in their microenvironment and to escape CTL detection. In contrast, NPC tumour cells show only rare expression of IL-6 and IL-8 and no detectable expression of IL-10 and TARC. Thus, the results suggest that the mechanisms employed by the EBV-positive tumour cells to escape immune recognition and destruction differ between HD and NPC.
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Affiliation(s)
- A Beck
- Institute for Pathology, Friedrich-Alexander-University, 91054 Erlangen, Germany
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24
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Abstract
The Epstein-Barr virus (EBV) is a herpes virus which establishes a life-long persistent infection in over 90% of the human adult population world-wide. Based on its association with a variety of lymphoid and epithelial malignancies, EBV has been classified as a group 1 carcinogen by the International Agency for Research on Cancer. In this article we discuss the evidence supporting an aetiological role for EBV in the pathogenesis of human tumours. The biology of EBV infection will be described with special emphasis on viral transforming gene products. A brief survey of EBV-associated tumours is followed by a discussion of specific problems. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated tumours also in patients without clinically manifest immunodeficiencies. Finally, the timing of EBV infection in the pathogenesis of virus-associated malignancies is discussed. There is good evidence that EBV infection precedes expansion of the malignant cell populations in some virus-associated tumours. However, this is clearly not always the case and for some of these tumours there are indications that clonal genetic alterations may occur prior to EBV infection. Thus, whilst there is good evidence to suggest that EBV is a human carcinogen, its precise role(s) in the development of virus-associated human tumours requires clarification.
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Affiliation(s)
- G Niedobitek
- Pathologisches Institut, Friedrich-Alexander-Universität, Krankenhausstr. 8-10, 91054 Erlangen, Germany. gerald.niedobitek @patho.imed.uni-erlangen.de
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25
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Abstract
The Epstein-Barr virus (EBV) is a herpes virus which establishes a life-long persistent infection in over 90% of the human adult population world-wide. Based on its association with a variety of lymphoid and epithelial malignancies, EBV has been classified as a group 1 carcinogen by the International Agency for Research on Cancer. In this article we discuss the evidence supporting an aetiological role for EBV in the pathogenesis of human tumours. The biology of EBV infection will be described with special emphasis on viral transforming gene products. A brief survey of EBV-associated tumours is followed by a discussion of specific problems. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated tumours also in patients without clinically manifest immunodeficiencies. Finally, the timing of EBV infection in the pathogenesis of virus-associated malignancies is discussed. There is good evidence that EBV infection precedes expansion of the malignant cell populations in some virus-associated tumours. However, this is clearly not always the case and for some of these tumours there are indications that clonal genetic alterations may occur prior to EBV infection. Thus, whilst there is good evidence to suggest that EBV is a human carcinogen, its precise role(s) in the development of virus-associated human tumours requires clarification.
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Affiliation(s)
- Gerald Niedobitek
- Pathologisches Institut, Friedrich-Alexander-UniversitätKrankenhausstr. 8–10, 91054 Erlangen, Germany
| | - Nadine Meru
- Pathologisches Institut, Friedrich-Alexander-UniversitätKrankenhausstr. 8–10, 91054 Erlangen, Germany
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26
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Tang KF, Tan SY, Chan SH, Chong SM, Loh KS, Tan LK, Hu H. A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma: implication for the intense tumor infiltration by T lymphocytes and macrophages. Hum Pathol 2001; 32:42-9. [PMID: 11172294 DOI: 10.1053/hupa.2001.20886] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is characterized by harboring Epstein-Barr virus genes in the tumor cells and an intense infiltration of leukocytes in the tumor tissue. These infiltrating cells are mainly composed of T lymphocytes and macrophages. The mechanism of this intense infiltration has long been a puzzle. We attempted to address this issue by studying the expression of CC chemokines, which are responsible for recruiting both T cells and macrophages, by an immunohistochemical approach. In biopsies obtained from nasopharynx of 17 NPC patients that contained tumor cells, expression of macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, macrophage chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, and RANTES was detected in the tumor-infiltrating cells, with MIP-1alpha and MCP-1 found in nearly all biopsies and the others relatively less frequently. Furthermore, expression of interferon-gamma (IFN-gamma) was also observed in tumor-infiltrating cells. In contrast, CC chemokines and IFN-gamma were rarely expressed in the 13 control biopsies that were either normal or with nonspecific inflammation, and in 4 biopsies from untreated NPC patients that contained no tumor cells. Using an immunofluorescent double-staining method, MIP-1alpha and MCP-1 were identified to be associated with macrophages, and IFN-gamma with T cells. Moreover, expression of CCR2 and CCR5, the receptors for these chemokines, was also detected in the tumor-infiltrating cells. These data indicate that the intense tumor infiltration by T cells and macrophages is a result of active recruitment. It seems possible that the intense infiltration of leukocytes in NPC tumor tissue is initiated by the activated tumor-reactive T cells. T cells migrate into the tumor tissue in an antigen-specific mode, and IFN-gamma secreted from these pioneer T cells activates tissue macrophages to express CC chemokines, especially MIP-1alpha and MCP-1, which consequently recruit more T cells and macrophages into the tumor tissue.
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MESH Headings
- Antibodies, Viral/blood
- Chemokines, CC/biosynthesis
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/immunology
- Humans
- Immunoglobulin A/blood
- Immunohistochemistry
- In Situ Hybridization
- Interferon-gamma/biosynthesis
- Lymphocytes, Tumor-Infiltrating/chemistry
- Lymphocytes, Tumor-Infiltrating/pathology
- Macrophages/chemistry
- Macrophages/pathology
- Nasopharyngeal Neoplasms/immunology
- Nasopharyngeal Neoplasms/metabolism
- Nasopharyngeal Neoplasms/pathology
- RNA, Viral/genetics
- Receptors, CCR2
- Receptors, CCR5/biosynthesis
- Receptors, Chemokine/biosynthesis
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Affiliation(s)
- K F Tang
- Department of Microbiology, Faculty of Medicine, National University of Singapore, Republic of Singapore
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27
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Niedobitek G. Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma. Mol Pathol 2000; 53:248-54. [PMID: 11091848 PMCID: PMC1186977 DOI: 10.1136/mp.53.5.248] [Citation(s) in RCA: 127] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2000] [Indexed: 12/14/2022]
Abstract
The association of nasopharyngeal carcinoma (NPC) with the Epstein-Barr virus (EBV) was firmly established as early as 1973. Nevertheless, the role for the virus in the pathogenesis of NPC is still controversial. In this article, the evidence implicating EBV in the development of NPC is reviewed, focusing on the cellular site of EBV persistence, the association of the virus with different NPC histotypes, the tumour cell phenotype in the context of viral latent gene expression, and the possible role of the lymphoid stroma.
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Affiliation(s)
- G Niedobitek
- Institute for Pathology, Friedrich-Alexander-University, Erlangen, Germany.
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28
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Margiotta V, Franco V, Rizzo A, Porter S, Scully C, Di Alberti L. Gastric and gingival localization of mucosa-associated lymphoid tissue (MALT) lymphoma. An immunohistochemical, virological and clinical case report. J Periodontol 1999; 70:914-8. [PMID: 10476901 DOI: 10.1902/jop.1999.70.8.914] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Non-Hodgkin's lymphomas (NHL) of the mucosa-associated lymphoid tissue (MALT) are characterized by their mucosal and glandular tissue localization. The case described here falls into the European-American classification of a low-grade B-cell lymphoma of the MALT type, with a gingival lesion 2 years after a gastric lesion. The pathogenetic mechanisms of NHL in oral MALT and the diagnosis and treatment are discussed.
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Affiliation(s)
- V Margiotta
- Department of Oral Medicine, University of Palermo, Italy.
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29
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Tsai ST, Fang SY, Jin YT, Su IJ, Yang BC. Analysis of the expression of Fas-L in nasopharyngeal carcinoma tissues. Oral Oncol 1999; 35:421-4. [PMID: 10645409 DOI: 10.1016/s1368-8375(99)00016-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial cancer with a high incidence in Southeast Asia. How it escapes attack from the host immune system is not fully understood. Recently, pieces of evidence show that Fas-ligand (Fas-L)-mediated apoptosis may be involved in immune privilege of tumours. To determine whether a similar mechanism may exist in NPC, the expression of Fas-L was analysed. Biopsy specimens of the nasopharynx were taken from 27 NPC patients. Histologically, they were either non-keratinizing or undifferentiated carcinomas. Nasopharyngeal biopsies of 11 other patients that proved to have no tumour served as control. The transcripts of Fas-L were detected by reverse transcription-polymerase chain reaction. Localization of Fas-L protein was performed with immunohistostaining using an antibody recognizing human Fas-L. All nasopharyngeal tissues have a similar amount of transcripts of Fas-L. However, the Fas-L protein was detected exclusively on the cell surface of malignant epithelial cells of NPC. The present findings suggest that Fas-L protein may be involved in evading immune attack of NPC.
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Affiliation(s)
- S T Tsai
- Department of Otolaryngology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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30
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Wong MP, Cheung KN, Yuen ST, Fu KH, Chan AS, Leung SY, Chung LP. Monocyte chemoattractant protein-1 (MCP-1) expression in primary lymphoepithelioma-like carcinomas (LELCs) of the lung. J Pathol 1998; 186:372-7. [PMID: 10209485 DOI: 10.1002/(sici)1096-9896(199812)186:4<372::aid-path204>3.0.co;2-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Lymphoepithelioma-like carcinoma (LELC) of the lung is a recently recognized primary non-small cell lung carcinoma with distinct clinicopathological features and an aetiological association with Epstein-Barr virus (EBV) infection. The tumour consists of clusters and sheets of poorly or undifferentiated tumour cells in close association with numerous mononuclear inflammatory cells, including a rich component of tumour-associated macrophages (TAMs). To investigate the molecular mechanism leading to the TAM-rich stroma, the expression of a monocyte-specific chemotactic and activating factor, monocyte chemoattractant protein-1 (MCP-1), was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH), and the presence of TAMs was demonstrated by immunohistochemistry in nine LELCs. The results were compared with those found in 17 conventional non-small cell lung carcinomas. RT-PCR showed specific MCP-1 amplification in both LELCs and non-LELCs, but ISH demonstrated a unique and extensive expression of MCP-1 transcripts by the tumour cells of LELCs only, while TAMs, stromal fibroblasts, and endothelial cells formed the major source of MCP-1 in non-LELCs. TAMs in LELCs were more abundant and showed a close topographical relationship with the MCP-1-expressing tumour cells. The results indicate that tumour cell expression of MCP-1 in LELCs is an important mechanism contributing to their distinctive morphological features. This is the first study that demonstrates the in vivo upregulation of a monocyte-specific chemokine by EBV-related carcinomas, illustrating an interesting aspect of tumour biology in EBV-related neoplasms.
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Affiliation(s)
- M P Wong
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong
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31
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Kojya S, Itokazu T, Noda Y, Ezaki M, Tomita Y, Ohsawa M, Aozasa K. Site-specific localization of Epstein-Barr virus in pharyngeal carcinomas. Jpn J Cancer Res 1998; 89:510-5. [PMID: 9685854 PMCID: PMC5921852 DOI: 10.1111/j.1349-7006.1998.tb03291.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
In this study, the correlations of factors with Epstein-Barr virus (EBV)-association were investigated in 50 patients with nasopharyngeal carcinoma (NPC), 61 with oropharyngeal carcinoma (OPC), and 55 with hypopharyngeal carcinoma (HPC) in Okinawa and Osaka prefectures in Japan. The incidence of pharyngeal carcinoma in Okinawa was previously found to be higher than that in Osaka; the incidence of OPC was approximately 6 times higher and that of HPC was two times higher. The EBV genome was detected in the tumor cells of the present patients; 83% of the Okinawa and 92% of the Osaka NPC patients. The EBV genome was not detected in OPC or HPC. A univariate analysis showed that sex, the location of the tumor, histology, and the degree of lymphocytic infiltration correlated with the EBV-positive rate. A multivariate analysis revealed that only the location of the tumor was independently correlated with the EBV-positive rate. Histology and tumor size were factors affecting the prognosis of the patients with NPC. The NPC of poorly differentiated type frequently showed the EBV genome, and NPC with lymphocytic infiltration showed a more favorable prognosis compared to the other NPC types. These findings suggest that latent genes of EBV expressed in cancer cells might trigger a cytotoxic T cell reaction against the cancer.
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Affiliation(s)
- S Kojya
- Department of Otorhinolaryngology, University of the Ryukyus, Faculty of Medicine, Okinawa
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32
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Judde JG, Spangler G, Magrath I, Bhatia K. Use of Epstein-Barr virus nuclear antigen-1 in targeted therapy of EBV-associated neoplasia. Hum Gene Ther 1996; 7:647-53. [PMID: 8845390 DOI: 10.1089/hum.1996.7.5-647] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
To target expression of toxic genes to Epstein-Barr virus (EBV)-associated tumor cells, we have developed an EBV-driven enzyme prodrug system (EDEPS) that takes advantage of the trans-activating properties of EBNA1, a latent protein expressed in all EBV-containing cells, to direct expression of cytosine deaminase (CD) at high levels in those cells only. Plasmids were constructed in which the CD gene or a luciferase reporter gene were cloned downstream of the herpes simplex virus thymidine kinase (tk) promoter and the family of repeats (FR) sequence from the oriP region of EBV. Analysis of luciferase activity after transient transfection into a panel of EBV-negative or -positive human cell lines showed that the presence of the FR element enhanced transcription from the tk promoter in all EBV-positive cell lines, whereas transcription from tk was repressed in all EBV-negative cell lines, including B, T, and fibroblast cell lines. In clonogenicity assays following transfection with the CD vector, the presence of 5-fluorocytosine (5-FC) in the culture medium completely abolished cell growth in EBV-positive cell lines, but did not affect the growth of EBV-negative cell lines. This vector system should have wide applicability in that it allows targeted expression of any gene of interest to tumors that carry EBV, irrespective of the role EBV plays in their pathogenesis.
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Affiliation(s)
- J G Judde
- Lymphoma Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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33
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Abstract
Hodgkin's disease represents a phenotypically and genotypically heterogeneous lymphoma of CD30-positive tumour cells. Infection of the putative tumour cell population with Epstein-Barr virus (EBV) represents the most common genetic abnormality detectable in HD, yet the role of EBV in the pathogenesis of HD is only poorly understood. In virus-associated HD cases, monoclonal EBV genomes are detectable in all Hodgkin and Reed-Sternberg (HRS) cells, indicating that EBV infection takes place before expansion of the HRS cell population and, by implication, supporting the concept of a monoclonal origin of HRS cells. EBV infection does not define a distinct subgroup of HD but is detectable in different histotypes and in HRS cells expressing lymphocyte differentiation antigens of different cell lineages. Through the EBV-encoded protein, LMP1, the virus may superimpose an activated phenotype on genotypically immature lymphocytes. EBV-induced modulation of the cytokine expression pattern of HRS cells may contribute to the local inhibition of EBV-specific immunity observed in EBV-positive cases.
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Affiliation(s)
- G Niedobitek
- Institute for Cancer Studies, University of Birmingham, U.K
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34
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Agathanggelou A, Niedobitek G, Chen R, Nicholls J, Yin W, Young LS. Expression of immune regulatory molecules in Epstein-Barr virus-associated nasopharyngeal carcinomas with prominent lymphoid stroma. Evidence for a functional interaction between epithelial tumor cells and infiltrating lymphoid cells. THE AMERICAN JOURNAL OF PATHOLOGY 1995; 147:1152-60. [PMID: 7573360 PMCID: PMC1871000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Undifferentiated nasopharyngeal carcinomas (UNPC) are characterized by an association with Epstein-Barr virus and an abundant lymphoid stroma. The role of this lymphoid stroma is uncertain but is mostly thought to represent an immune response against viral or tumor antigens. We have analyzed the expression of immune regulatory receptor/ligand pairs in snap-frozen biopsies of 20 UNPCs. All cases were Epstein-Barr virus positive and the virus-encoded latent membrane protein, LMP1, was expressed in 6 cases. By immunohistochemistry, we have demonstrated the expression of CD70 and CD40 in the tumor cells of 16 and 18 cases, respectively. Infiltrating lymphoid cells expressing CD27, the CD70 receptor, and the CD40 ligand were present in all cases. The Bcl-2 protein was detected in 17 cases. Unexpectedly, tumor cells of 5 cases expressed at least one member of the B7 family (CD80, CD86, and B7-3) and many lymphoid cells expressing the corresponding counter-receptor, CD28, were detected in all cases. Interestingly, 5 of 6 LMP1-positive cases also expressed B7, whereas all 14 LMP1-negative cases were also B7 negative. Our results indicate that T cells and carcinoma cells communicate in the microenvironment of UNPCs and suggest that the presence of a lymphoid stroma may be a requirement for UNPC growth at least in certain stages of tumor development.
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Affiliation(s)
- A Agathanggelou
- Department of Pathology, University of Birmingham, United Kingdom
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35
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Karran L, Jones M, Morley G, van Noorden S, Smith P, Lampert I, Griffin BE. Expression of a B-cell marker, CD24, on nasopharyngeal carcinoma cells. Int J Cancer 1995; 60:562-6. [PMID: 7829271 DOI: 10.1002/ijc.2910600422] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Random sequencing of clones from a lambda gt10 cDNA library, made from mRNA expressed in an Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) has revealed the gene transcript of human CD24. The CD24 antigen, a glycosylphosphatidylinositol-anchored cell surface molecule, has been identified as a B-cell marker that is lost during cell maturation. We show here that it is expressed on 3 NPC xenografts, previously defined as consisting of poorly differentiated epithelial cells, and on an NPC biopsy. In the case of the former, the level of expression of CD24 corresponds to the EBV load. A B-lymphoblastoid cell line carrying the same EBV genome as one of the tumours, C15, and an EBV-negative Burkitt's lymphoma cell line do not display the antigen, but epithelial-like cells of a laryngeal tumour cell line (Hep2) do express it. Our data suggest that CD24 may be a marker of cell differentiation not only for B cells but also for epithelial cells and may have an indirect association with EBV gene expression.
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MESH Headings
- Animals
- Antigens, CD/biosynthesis
- Antigens, CD/genetics
- Antigens, Neoplasm/biosynthesis
- Antigens, Neoplasm/genetics
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- Base Sequence
- Blotting, Northern
- CD24 Antigen
- Cell Differentiation
- DNA Primers
- DNA, Neoplasm/genetics
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Viral
- Herpesvirus 4, Human/immunology
- Humans
- Immunohistochemistry
- Membrane Glycoproteins
- Mice
- Mice, Nude
- Molecular Sequence Data
- Nasopharyngeal Neoplasms/immunology
- Nasopharyngeal Neoplasms/virology
- RNA, Messenger/analysis
- RNA, Neoplasm/analysis
- Tumor Cells, Cultured/immunology
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Affiliation(s)
- L Karran
- Department of Virology, Royal Postgraduate Medical School, London, UK
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36
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Karran L, Gao Y, Smith PR, Griffin BE. Expression of a family of complementary-strand transcripts in Epstein-Barr virus-infected cells. Proc Natl Acad Sci U S A 1992; 89:8058-62. [PMID: 1325642 PMCID: PMC49855 DOI: 10.1073/pnas.89.17.8058] [Citation(s) in RCA: 51] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
A major family of polyadenylylated cytoplasmic transcripts are expressed from the BamHI A-I region of the Epstein-Barr virus genome, off the strand complementary to that encoding several functions associated with viral replication and the lytic cycle, including the DNA polymerase (BALF-5). These complementary-strand transcripts (the main one is about 4.8 kilobases long), expressed in all cell types associated with Epstein-Barr virus, are present at high levels in nasopharyngeal carcinoma tumors. Sequence analysis of clones that correspond to spliced transcripts in a cDNA library from such a tumor, C15, generates a profile of the main complementary mRNA. It contains at least three AUG-initiated open reading frames, the largest of which could be translated to give a polypeptide of about 20 kDa. Evidence from several types of experiments suggests that conditions which support the up (or down) regulation of transcriptional expression from one viral DNA strand within the relevant region of the genome produce the opposite effect on transcripts from the other strand. The capacity for interference between complementary Epstein-Barr viral transcripts offers a mechanism for control of gene expression that may be related to maintenance of viral latency.
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Affiliation(s)
- L Karran
- Department of Virology, Royal Postgraduate Medical School, London, United Kingdom
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37
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Mahé Y, Hirose K, Clausse B, Chouaib S, Tursz T, Mariamé B. Heterogeneity among human nasopharyngeal carcinoma cell lines for inflammatory cytokines mRNA expression levels. Biochem Biophys Res Commun 1992; 187:121-6. [PMID: 1325786 DOI: 10.1016/s0006-291x(05)81467-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Using polymerase chain reaction (PCR), we confirmed the expression of interleukin-1 alpha (IL-1 alpha) by the human nasopharyngeal carcinoma (NPC) cell line C15 without contribution of either human IL-1 beta or mouse IL-1 alpha in the biological activity previously found in C15. However we showed that IL-1 alpha was not expressed in all NPCs. IL-1 beta and/or tumor necrosis factor (TNF)-alpha genes could also be activated, independently from the number of Epstein Barr Virus (EBV) copies harbored by the cells. Interestingly, the primary tumor C15 showed a profile of TNF-sensitive tumor while C17, C18 and C19 which were derived from metastasis have a typical profile of TNF-resistant cells. Furthermore, the inflammatory cytokines whose genes are classically induced by IL-1 and TNF were found expressed only in C17 and C19 suggesting another level of heterogeneity among NPCs.
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Affiliation(s)
- Y Mahé
- Laboratoire de Biologie des Tumeurs Humaines, URA 1156 CNRS, Institut Gustave Roussy, Villejuif, France
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38
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Busson P, Zhang Q, Guillon JM, Gregory CD, Young LS, Clausse B, Lipinski M, Rickinson AB, Tursz T. Elevated expression of ICAM1 (CD54) and minimal expression of LFA3 (CD58) in epstein-barr-virus-positive nasopharyngeal carcinoma cells. Int J Cancer 1992; 50:863-7. [PMID: 1372880 DOI: 10.1002/ijc.2910500605] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is a remarkable entity among human tumors because of its constant association with the Epstein-Barr virus (EBV). Malignant epithelial cells harbor the EBV genome and often express at least 2 species of latent EBV protein (EBNA1 and LMP1). Despite the massive presence of tumor-infiltrating lymphocytes, NPC cells obviously escape immune surveillance directed to EBV antigens. Previous investigations carried out on EBV-positive Burkitt lymphoma (BL) cells have shown that this fact may be partially accounted for by a lack of expression of ICAM1 (CD54) and LFA3 (CD58). ICAM1 and LFA3 have therefore been investigated in fresh NPC biopsies and transplanted NPCs. With only 1 exception out of 9 cases, NPC cells appear to express high levels of ICAM1 and low levels of LFA3. This is a complete inversion of the pattern observed in normal epithelial cells in vivo. Additional investigations will be required to determine to what extent these characteristics affect T-cell interactions with NPC cells, specially in the process of EBV-antigen recognition.
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MESH Headings
- Animals
- Antibodies, Monoclonal
- Antigens, CD/analysis
- Antigens, Surface/analysis
- CD58 Antigens
- Cell Adhesion Molecules/analysis
- Cell Adhesion Molecules/genetics
- Cell Line
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/isolation & purification
- Histocompatibility Antigens Class I/analysis
- Humans
- Intercellular Adhesion Molecule-1
- Membrane Glycoproteins/analysis
- Mice
- Mice, Nude
- Nasopharyngeal Neoplasms/immunology
- Nasopharyngeal Neoplasms/microbiology
- Nasopharyngeal Neoplasms/pathology
- Nasopharyngeal Neoplasms/surgery
- Neoplasm Transplantation
- Receptors, Virus/analysis
- Transcription, Genetic
- Transplantation, Heterologous
- Tumor Cells, Cultured
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Affiliation(s)
- P Busson
- Laboratoire de Biologie des Tumeurs Humaines, URA 1156 CNRS, Institut Gustave Roussy, Villejuif, France
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39
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Cvitkovic E, Bachouchi M, Armand JP. Nasopharyngeal Carcinoma: Biology, Natural History, and Therapeutic Implications. Hematol Oncol Clin North Am 1991. [DOI: 10.1016/s0889-8588(18)30418-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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40
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Smith PR, Griffin BE. Differential expression of Epstein Barr viral transcripts for two proteins (TP1 and LMP) in lymphocyte and epithelial cells. Nucleic Acids Res 1991; 19:2435-40. [PMID: 1710355 PMCID: PMC329454 DOI: 10.1093/nar/19.9.2435] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Studies presented here show that some functions of the human herpesvirus, EBV, may be transcriptionally differentially expressed in two cell types which carry the same (C15) isolate of this virus. Of the 'latent' viral functions investigated, only one (TP2) of the episomally-specific genes that encode terminal proteins (TP1 and TP2) is found to be expressed in the C15 epithelial cell tumour environment, whereas both are transcribed--as different, but related, messengers--in a B-cell line generated with virus from the C15 tumour. The other gene investigated is that for latent membrane protein (LMP), which is found in the same region of the EBV genome but on the opposite strand. This gene, apparently transcriptionally silent in B-cell (Burkitt's) lymphomas, is expressed in the C15 epithelial tumour, as well as in other nasopharyngeal carcinomas investigated. Promoter usage in the carcinomas and B-cells appears, in some cases at least, to be cell-type specific. Expression may also be governed by methylation since a chromosomally silent region in the carcinoma (that encompassing TP1) is highly methylated on CpG residues, whereas the active region (encoding TP2 and LMP) is virtually free of such methylation. Our data suggest that there may be selective transcriptional regulation of EBV genes in the two types of cells investigated. Thus, it may be unnecessary to invoke different virus genotypes to account for the two distinct malignancies--Burkitt's lymphoma and nasopharyngeal carcinoma--associated with EBV.
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Affiliation(s)
- P R Smith
- Department of Virology, Royal Postgraduate Medical School, London, UK
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41
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Lakhdar M, Ben Aribia MH, Maalej M, Ladgham A. Selective homing of phenotypically lytic cells within nasopharyngeal carcinoma biopsies: numerous CD8- and CD16-positive cells in the tumor. Int J Cancer 1991; 48:57-61. [PMID: 1826899 DOI: 10.1002/ijc.2910480111] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
We present a comparative analysis of cell-mediated immunity between circulating lymphocytes and tumor-infiltrating lymphocytes (TIL) from patients with nasopharyngeal carcinoma (NPC). Phenotypic analysis using a panel of monoclonal antibodies (MAbs) to define lymphocytic subsets has revealed a selective homing of phenotypically lytic cells such as CD8- and CD16-positive cells, but a low percentage of macrophages when compared to PBL of NPC patients. Also, PBL and TIL contain an equivalent percentage of activated T-lymphocytes expressing HLA-DR molecules and IL-2 receptors. Functionally, TIL exhibit an abolished NK-cell activity and concomitant decrease of proliferative response to phytohemagglutinin (PHA) and concanavalin A (ConA) stimulation when compared with PBL.
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Affiliation(s)
- M Lakhdar
- Unité de Recherche d'Immunologie Cellulaire, Hôpital Militaire Principal d'Instruction de Tunis, Tunisia
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42
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Ferradini L, Miescher S, Stoeck M, Busson P, Barras C, Cerf-Bensussan N, Lipinski M, von Fliedner V, Tursz T. Cytotoxic potential despite impaired activation pathways in T lymphocytes infiltrating nasopharyngeal carcinoma. Int J Cancer 1991; 47:362-70. [PMID: 1899651 DOI: 10.1002/ijc.2910470309] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial tumor consistently associated with EBV. The histological picture is characterized by a strikingly abundant lymphocytic infiltrate. Furthermore, the epithelial tumor cells present several immunological characteristics which suggest an important role for tumor-infiltrating lymphocytes (TIL) in the biology of this tumor. The present study reports the phenotypic and functional characterization of TIL from NPC obtained after enzymatic digestion of 15 NPC biopsies. Flow cytometric analysis of TIL suspensions indicated that most TIL were mature CD3+ T lymphocytes (mean = 60%) with a variable CD4/CD8 ratio. Most TIL were TCR alpha/beta-positive (mean = 55%) and only a few TCR gamma-delta-positive cells could be identified. A small percentage (mean = 9%) displayed an activated phenotype (CD25+, HLA class II+). Using limiting dilution analysis, we found that the average frequency of proliferative T-lymphocyte precursors (PTL-P) is lower among TIL (1/40) than in autologous (1/7) or normal PBL (1/1.4). Moreover, sorting experiments have shown that this defect is significantly more pronounced in the CD8+ than in the CD4+ TIL subset. Accordingly, the TCR and the CD2-mediated antigen-independent pathways of activation were impaired. Different types of cytotoxic precursor could be detected. These included lectin-dependent cell cytotoxicity (LDCC) and NK-like or lymphokine-activated killer (LAK) activity. Interestingly, some TIL from NPC were able to lyse an NPC tumor (C15) maintained in nude mice. Thus, despite impaired activation pathways, the cytolytic potential of proliferating TIL in NPC is preserved.
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Affiliation(s)
- L Ferradini
- Laboratoire d'Immunobiologie des Tumeurs, U.A. 1156 C.N.R.S. Institut Gustav Roussy, Villejuif, France
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43
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Gasmi J, Bachouchi M, Cvitkovic E, Boussen H, Azli N, Rahal M, Domenge C, Wibault P, Eschwege F, Schwaab G. Nasopharyngeal carcinoma: a medical oncology viewpoint. The Gustave Roussy experience. Ann Oncol 1990; 1:245-53. [PMID: 1702311 DOI: 10.1093/oxfordjournals.annonc.a057741] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Affiliation(s)
- J Gasmi
- Department of Medicine, Institut Gustave Roussy, Villejuif, France
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44
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Colburn NH, Raab-Traub N, Becker D, Cao Y, Winterstein D. Transforming activity of nasopharyngeal carcinoma DNA detectable in mouse JB6 cells. Int J Cancer 1989; 44:1012-6. [PMID: 2558076 DOI: 10.1002/ijc.2910440613] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A JB6 mouse epidermal recipient cell line has been used to detect nasopharyngeal carcinoma (NPC) DNA-associated transforming activity that is not detectable in the NIH 3T3 focus assay. NPC DNA showed both transforming activity and activity for transferring sensitivity to tumor-promoter-induced neoplastic transformation, assayed in 2 different variants of mouse JB6 cells. Comparison of DNAs from various NPC sources that did or did not harbor EBV DNA and that varied in degree of differentiation showed similar transforming activities and similar activities for transferring promotion sensitivity. Thus both a NPC DNA-associated promotion sensitivity and an oncogenic activity function independently of concurrent EBV gene expression.
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Affiliation(s)
- N H Colburn
- Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick, MD 21701
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45
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Billaud M, Busson P, Huang D, Mueller-Lantzch N, Rousselet G, Pavlish O, Wakasugi H, Seigneurin JM, Tursz T, Lenoir GM. Epstein-Barr virus (EBV)-containing nasopharyngeal carcinoma cells express the B-cell activation antigen blast2/CD23 and low levels of the EBV receptor CR2. J Virol 1989; 63:4121-8. [PMID: 2550660 PMCID: PMC251025 DOI: 10.1128/jvi.63.10.4121-4128.1989] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Anaplastic nasopharyngeal carcinoma (NPC) cells invariably harbor the Epstein-Barr virus (EBV) genome, an association that is unique among human virus-associated cancers. Although EBV is able to replicate in epithelial cells, results with expression of the EBV receptor (complement receptor type 2 [CR2]; also called CD21) in normal and malignant epithelial cells are conflicting. We grew five different EBV-associated NPC tumors in nude mice, and by using a sensitive transcriptional assay, we detected a very weak transcription signal of the EBV receptor CR2 gene in these cells. This suggests that low levels of EBV receptor may be expressed by malignant epithelial nasopharyngeal cells. The gene coding for Blast2/CD23, a B-cell activation molecule induced by EBV, was transcribed in three of the transplanted NPC tumors. The soluble form of the Blast2/CD23 protein was also detected in medium taken from short-term cultures of the same NPC cell lines. In contrast to the lymphoid system, in which Blast2/CD23 expression is associated with EBV nuclear antigen (EBNA2) expression, no EBNA2 protein could be detected in these NPC epithelial cells. Our study represents the first demonstration of Blast2/CD23 expression in epithelial cells. As the soluble form of the Blast2/CD23 protein possesses growth factor activity associated with EBV-induced B-cell immortalization, these results suggest a possible role for this molecule in the pathogenesis of NPC.
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MESH Headings
- Animals
- Antigens, Differentiation, B-Lymphocyte/analysis
- Antigens, Differentiation, B-Lymphocyte/genetics
- Antigens, Viral/analysis
- Antigens, Viral/genetics
- Carcinoma/immunology
- Epstein-Barr Virus Nuclear Antigens
- Herpesvirus 4, Human/genetics
- Humans
- Mice
- Nasopharyngeal Neoplasms/immunology
- Neoplasm Transplantation
- RNA, Messenger/analysis
- Receptors, Complement/analysis
- Receptors, Complement/genetics
- Receptors, Complement 3d
- Receptors, Fc/analysis
- Receptors, Fc/genetics
- Receptors, IgE
- Transcription, Genetic
- Transplantation, Heterologous
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Affiliation(s)
- M Billaud
- International Agency for Research on Cancer, Lyon, France
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46
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Abstract
Interleukin-1 alpha and interleukin-1 beta are 17.5 kDa peptides which exert a wide variety of biological activities. Both forms of interleukin bind to a common 60-70 kDa receptor expressed by most somatic cells. One major effect of interleukin-1 is to induce the expression of other genes, including genes for other interleukins (IL-6), colony stimulating factors (GM-CSF and G-CSF) and growth factors (PDGFA) and adhesion proteins (ELAM-1, ICAM-1). In vitro, cells of the hematopoietic stroma including thymic epithelium, endothelial cells, fibroblasts, T-lymphocytes, and macrophages, are all capable of responding to interleukin-1 by expressing most of these IL-1 inducible genes. Accordingly, because interleukin-1 has no direct effect on hematopoietic progenitor cells, its major effect on hematopoiesis is to regulate the expression of hematopoietic growth factor genes by other cells. The mechanism by which interleukin-1 induces gene expression is to first induce mRNA accumulation which accounts for an increase in translation of the mRNA. The accumulation of RNA, interestingly, does not result from increased transcription of these genes but by the stabilization of the mRNA. Ordinarily, the hematopoietic growth factor gene transcripts have a very short half-life but in an interleukin-1 induced cell, the half-life of these transcripts is markedly prolonged (greater than 24 h). This particular effect of IL-1 on transcript stability likely accounts for virtually all of the hematopoietic activities of interleukin-1 including: (1) induction of growth factors; (2) synergy with other factors; (3) priming; and (4) auto-induction. Three clinical models of hematopoiesis are presented which suggest that the interleukin-1 CSF network is operative in vivo. The ability of interleukin-1 to induce the expression of hematopoietic growth factor genes as well as genes whose products regulate cellular function and traffic suggest that interleukin-1 is an essential molecular master switch for a number of cellular responses occurring in organisms facing the vicissitudes of their environment.
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Affiliation(s)
- G C Bagby
- Oregon Health Sciences University, Portland
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47
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Cvitkovic E, Boussen H, Armand JP. Nasopharyngeal cancer, undifferentiated type: the medical oncologist's viewpoint. Cancer Treat Res 1989; 42:175-211. [PMID: 2577103 DOI: 10.1007/978-1-4613-1747-0_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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48
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Busson P, Ganem G, Flores P, Mugneret F, Clausse B, Caillou B, Braham K, Wakasugi H, Lipinski M, Tursz T. Establishment and characterization of three transplantable EBV-containing nasopharyngeal carcinomas. Int J Cancer 1988; 42:599-606. [PMID: 2971626 DOI: 10.1002/ijc.2910420422] [Citation(s) in RCA: 176] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Three transplantable nasopharyngeal carcinoma (NPC) tumors, designated C15, C17 and C18, have been obtained and characterized. C15, derived from a primary NPC tumor, has been propagated in nude mice for 30 passages. C17 and C18, derived from metastatic NPC tissue, have been passaged 10 times. Desmosomes, present in every case, provided confirmation of the epithelial origin of all 3 tumors. The Epstein-Barr virus (EBV) genome is contained in C15, C18 and C17 tumor cells with 30, 12 and 3 copies, respectively. The Epstein-Barr virus nuclear antigen (EBNA) was stained by the classical anti-complement immunofluorescence (ACIF) technique. Fluorescence intensity was strong in C15, moderate in C18, and hardly detectable in C17 cells. No expression of the EA and VCA antigens was detected. Flow cytometry analysis performed on monocellular suspensions showed the absence of detectable CR2 molecules (the EBV receptor on B lymphocytes) in all 3 tumors, and the constitutive expression of HLA class-II antigens in C15 and C17 cells. IL-1 activity was demonstrated in the supernatant of C15 and C17 cells cultivated in vitro for 3 days. These data confirm that the constitutive synthesis of MHC class-II molecules and the release of IL-1-like activities are frequent features of NPC cells. These characteristics could be of importance in relation with the T-cell infiltrate found in NPC primary tumors.
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Affiliation(s)
- P Busson
- Laboratoire d'Immunobiologie des Tumeurs, U.A. 1156 C.N.R.S., Institut Gustave Roussy, Villejuif, France
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49
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Shaw JE, Baglia LA, Leung K. Maintenance of growth transformation with Epstein-Barr virus is mediated by secretion of autocrine growth factors in two serum-free B-cell lines. J Virol 1988; 62:3415-21. [PMID: 2841494 PMCID: PMC253465 DOI: 10.1128/jvi.62.9.3415-3421.1988] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The characteristics of two tamarin (Saguinus oedipus) B-cell lines (sfBIT and sfBT) growth-transformed by Epstein-Barr virus (EBV) that proliferate continuously in serum-free medium are described. sfBIT was established by selecting cells for growth in RPMI 1640 supplemented with insulin, transferrin, and selenium (J. E. Shaw, R. G. Petit, and K. Leung, J. Virol. 61:4033-4037, 1987). sfBT, a subline of sfBIT cells reported here for the first time, required transferrin as the only protein supplement for continuous growth in RPMI 1640. Growth of sfBT cells was linear with human transferrin at 10(-2) to 10 micrograms/ml. Transferrin at 5 micrograms/ml yielded a culture density of 5 X 10(5) to 1 X 10(6) cells per ml, a cell doubling time of 2 to 3 days, and a culture viability greater than 95%. sfBIT and sfBT cells released transforming virus during continuous growth in serum-free culture medium without EBV-inducing agents. The spent medium of both serum-free lines supported cell growth at low culture density (1 x 10(4) to 5 X 10(4) cells per ml), but growth was arrested at low culture density with fresh serum-free medium. A procedure to measure growth-promoting activity (GPA) was established, and it revealed that the GPA of spent medium was greater than that of fresh medium for both serum-free cell lines. When fresh and spent media were dialyzed (molecular weight cutoff, 3,500) and subsequently concentrated by lyophilization, only the GPA of spent medium increased. We conclude that maintenance of growth transformation of tamarin cells latently infected with EBV is mediated by growth factors that are entirely autocrine in origin.
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Affiliation(s)
- J E Shaw
- Department of Medical Microbiology and Immunology, College of Medicine, Ohio State University, Columbus 43210-1239
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50
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Klein C, Busson P, Tursz T, Young LS, Raab-Traub N. Expression of the c-fgr related transcripts in Epstein-Barr virus-associated malignancies. Int J Cancer 1988; 42:29-35. [PMID: 2839429 DOI: 10.1002/ijc.2910420107] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The proto-oncogene c-fgr is expressed at high levels in cell lines derived from lymphomas which are infected with Epstein-Barr virus (EBV) (Cheah et al., 1986). mRNA extracted directly from biopsies of EBV-infected tissues was analyzed on Northern blots to determine if c-fgr is expressed during lympho-proliferations induced in vivo by EBV and in nasopharyngeal carcinoma (NPC), the epithelial malignancy associated with the virus. Elevated levels of c-fgr expression were detected in all EBV-positive lympho-proliferations in vivo but not in cell lines established by EBV infection in vitro. This indicates that the induction of the c-fgr proto-oncogene is not an essential component of EBV-induced transformation. Although no c-fgr expression was detected in EBV-positive or -negative epithelial cell lines, the 3.0-kb c-fgr mRNA was detected at low levels in mRNA obtained from NPC biopsy specimens. However, NPC tissue, after passage in nude mice (which eliminates infiltrating lymphoid and myeloid cells) did not contain the 3.0-kb c-fgr mRNA. The absence of expression of c-fgr in the malignant epithelial cells infected with EBV contrasts with the elevated level of the proto-oncogene in EBV-infected lymphoma tissue and cell lines established from lymphomas. This suggests differences in the expression of cellular functions in EBV-induced malignancies of these 2 distinct cell types.
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Affiliation(s)
- C Klein
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill 27514
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