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Ruan L, Wang L. Adoptive cell therapy against tumor immune evasion: mechanisms, innovations, and future directions. Front Oncol 2025; 15:1530541. [PMID: 40094019 PMCID: PMC11906336 DOI: 10.3389/fonc.2025.1530541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/06/2025] [Indexed: 03/19/2025] Open
Abstract
Tumors employ a range of strategies to evade detection and eradication by the host's immune system. These include downregulating antigen expression, altering antigen presentation processes, and inhibiting immune checkpoint pathways. etc. Adoptive Cell Therapy (ACT) represents a strategy that boosts anti-tumor immunity. This is achieved by amplifying or genetically engineering immune cells, which are either sourced from the patient or a donor, in a laboratory setting. Subsequently, these cells are reintroduced into the patient to bolster their immune response against cancer. ACT has successfully restored anti-tumor immune responses by amplifying the activity of T cells from patients or donors. This review focuses on the mechanisms underlying tumor escape, including alterations in tumor cell antigens, the immunosuppressive tumor microenvironment (TME), and modulation of immune checkpoint pathways. It further explores how ACT can avddress these factors to enhance therapeutic efficacy. Additionally, the review discusses the application of gene-editing technologies (such as CRISPR) in ACT, highlighting their potential to strengthen the anti-tumor capabilities of T cells. Looking forward, the personalized design of ACT, combined with immune checkpoint inhibitors and targeted therapies, is expected to significantly improve treatment outcomes, positioning this approach as a key strategy in the field of cancer immunotherapy.
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Affiliation(s)
- Liqin Ruan
- Department of Hepatobiliary Surgery, JiuJiang City Key Laboratory of Cell Therapy, JiuJiang No.1 People's Hospital, Jiujiang, Jiangxi, China
| | - Lu Wang
- Department of Oncology, JiuJiang City Key Laboratory of Cell Therapy, JiuJiang No.1 People's Hospital, Jiujiang, Jiangxi, China
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Zhou X, Zhang B, Hu J, Shen J, Chen Z, Zhang J, Wu B, Zhou E, Peng S, Wong TW, Yang G, Cao J, Chen M. Igniting cold tumors of intrahepatic cholangiocarcinoma: An insight into immune evasion and tumor immune microenvironment. THE INNOVATION MEDICINE 2024; 2:100052. [DOI: 10.59717/j.xinn-med.2024.100052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
<p>Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer that originates from the epithelium of the intrahepatic bile duct. The various treatments for ICC, such as chemotherapy, radiotherapy, and locoregional therapy, confer only modest improvements in survival rates. Immunotherapy, although revolutionary in cancer treatment, has found limited application in the treatment of ICCs due to the “cold” nature of these tumors, which is marked by scant T-cell infiltration. This characteristic makes immune checkpoint inhibitors (ICIs) unsuitable for the majority of ICC patients. Therefore, comprehensively understanding the mechanisms underlying these “cold” tumors is crucial for harnessing the potential of immunotherapy for treating ICC patients. This paper explores immune evasion mechanisms and the complex tumor immune microenvironment of ICC. This study provides a comprehensive overview of therapeutic strategies aimed at activating cold tumors and enhancing their immunogenicity. Furthermore, potential and promising targets for cancer vaccines and adoptive cellular therapy in the context of ICC are discussed. This endeavor strives to reveal new pathways for innovative immunotherapy strategies, with a focus on overcoming the key challenge of triggering an effective immune response in ICC patients.</p>
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Li C, Bie L, Chen M, Ying J. Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:1310-1327. [PMID: 38213535 PMCID: PMC10776604 DOI: 10.37349/etat.2023.00199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/09/2023] [Indexed: 01/13/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive type of adenocarcinoma distinguished by its invasiveness. Depending on specific anatomical positioning within the biliary tree, CCA can be categorized into intrahepatic CCA (ICCA), perihilar CCA (pCCA) and distal CCA (dCCA). In recent years, there has been a significant increase in the global prevalence of CCA. Unfortunately, many CCA patients are diagnosed at an advanced stage, which makes surgical resection impossible. Although systemic chemotherapy is frequently used as the primary treatment for advanced or recurrent CCA, its effectiveness is relatively low. Therefore, immunotherapy has emerged as a promising avenue for advancing cancer treatment research. CCA exhibits a complex immune environment within the stromal tumor microenvironment (TME), comprising a multifaceted immune landscape and a tumor-reactive stroma. A deeper understanding of this complex TME is indispensable for identifying potential therapeutic targets. Thus, targeting tumor immune microenvironment holds promise as an effective therapeutic strategy.
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Affiliation(s)
- Chaoqun Li
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, Zhejiang, China
| | - Lei Bie
- Department of Thoracic Surgery, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Muhua Chen
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
| | - Jieer Ying
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
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Annuar AA, Ankathil R, Mohd Yunus N, Husin A, Ab Rajab NS, Abdul Aziz AA, Ibrahim MI, Sulong S. Impact of Fas/Fasl Gene Polymorphisms on Susceptibility Risk and Imatinib Mesylate Treatment Response in Chronic Myeloid Leukaemia Patients. Asian Pac J Cancer Prev 2021; 22:565-571. [PMID: 33639675 PMCID: PMC8190357 DOI: 10.31557/apjcp.2021.22.2.565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Indexed: 12/03/2022] Open
Abstract
Background: The FAS mediated apoptosis pathway involving the FAS and FASL genes plays a crucial role in the regulation of apoptotic cell death and imatinib mesylate (IM) mechanism of action. Promoter polymorphisms FAS-670 A>G and FAS-844 T>C which alter the transcriptional activity of these genes may grant a risk to develop cancer and revamp the drug activities towards the cancer cell. We investigated the association of these two polymorphisms with the susceptibility risk and IM treatment response in Malaysian chronic myeloid leukaemia (CML) patients. Methods: This is a retrospective study, which included 93 CML patients and 98 controls. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method was used to genotype the FAS and FASL polymorphisms. Data nanlysis was done using SPSS Version 22. The associations of the genotypes with susceptibility risk and IM response in CML patients were assessed by means of logistic regression analysis and deriving odds ratio with 95% CI. Results: We observed a significant association between FASL-844T>C polymorphism and CML susceptibility risk and IM response. Variant C allele and FASL-844 CC variant genotype carriers had significantly higher risk for CML susceptibility (OR 1.756, CI 1.163-2.652, p=0.007 and OR 2.261, CI 1.013-5.047, p=0.047 respectively). Conversely, the heterozygous genotype FASL-844 TC conferred lower risk for CML susceptibility (OR 0.379, CI 0.176-0.816, p=0.013). The heterozygous and homozygous variant genotypes and variant C alleles were found to confer a lower risk for the development of IM resistance with OR 0.129 (95% CI: 0.034-0.489 p=0.003), OR 0.257 (95% CI: 0.081-0.818, p=0.021), and OR 0.486 (95% CI: 0.262-0.899, p=0.021) respectively. We also found that FAS-670 A>G polymorphism was not associated with CML susceptibility risk or IM response. Conclusion: The genetic polymorphism FASL-844 T>C may contribute to the CML susceptibility risk and also IM treatment response in CML patients. Accodringly, it may be useful as a biomarker for predicting CML susceptibility risk and IM resistance.
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Affiliation(s)
- Aziati Azwari Annuar
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Ravindran Ankathil
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Nazihah Mohd Yunus
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Azlan Husin
- Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kelantan Malaysia
| | - Nur Shafawati Ab Rajab
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Ahmad Aizat Abdul Aziz
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Mohd Ismail Ibrahim
- Department of Community Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Sarina Sulong
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
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Zhao T, Li W, Chen J, Qin W. Genomic variants in Fas-mediated apoptosis pathway predict a poor response to Platinum-based Chemotherapy for Chinese Gastric Cancer Patients. J Cancer 2021; 12:849-859. [PMID: 33403042 PMCID: PMC7778532 DOI: 10.7150/jca.48120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 02/09/2020] [Indexed: 12/16/2022] Open
Abstract
Platinum-based adjuvant chemotherapy is very common for gastric cancer (GC) patients, but the chemotherapy sensitivity is very heterogeneous. The genomic variants and the gene-gene interactions involved in Fas-mediated apoptosis pathway including Fas (FAS 1377 G > A and 670 A > G), FasL (FASL 844 C > T) and caspase-8 (CASP8 -652 6N ins > del or I > D), may paly vital roles in the response to platinum-based treatment. In our investigation, 662 stage II-III postoperative GC patients were enrolled between 1998 and 2006. 261 patients accepted platinum-based regimens and the remaining 401 were not. The log rank tests, Kaplan Meier plots, Pearson chi-square tests, Student t-tests and Cox regression analyses were performed. For the chemotherapy cohort, FAS 1377 G > A or FAS 670 A > G variants alone was related with inferior survival, and a greater than additive effect was identified when patients simultaneously carrying FAS 1377 GA and FAS 670 GA genotypes. But the poor response was neutralized when patients simultaneously carrying FASL 844 C > T or CASP8 -652 6N ins > del mutations. Our study suggested that FAS 1377 G > A and FAS 670 A > G variants may serve as potential biomarkers to predict the response to platinum-based adjuvant chemotherapy, and the gene-gene interactions involved in Fas-mediated apoptosis pathway may enhance or neutralize the chemosensitivity.
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Affiliation(s)
- Tingting Zhao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 21000, China
| | - Wei Li
- Department of Gynecology, Zhenjiang Maternity and Childcare Hospital, Zhenjiang, 212000, China
| | - Jinfei Chen
- Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, 21000, China
| | - Weisong Qin
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 21000, China
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Dardiotis E, Siokas V, Garas A, Paraskevaidis E, Kyrgiou M, Xiromerisiou G, Deligeoroglou E, Galazios G, Kontomanolis EN, Spandidos DA, Tsatsakis A, Daponte A. Genetic variations in the SULF1 gene alter the risk of cervical cancer and precancerous lesions. Oncol Lett 2018; 16:3833-3841. [PMID: 30127996 PMCID: PMC6096185 DOI: 10.3892/ol.2018.9104] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 06/29/2018] [Indexed: 12/16/2022] Open
Abstract
Human papillomavirus (HPV) infection alone is not sufficient to explain the development of cervical cancer. Genetic variants have been linked to the development of precancerous lesions and cervical cancer. In this study, we aimed to evaluate the association of 10 single nucleotide polymorphisms (SNPs) of the Fas cell surface death receptor (FAS), trinucleotide repeat containing 6C (TNRC6C), transmembrane channel like 8 (TMC8), DNA meiotic recombinase 1 (DMC1), deoxyuridine triphosphatase (DUT), sulfatase 1 (SULF1), 2′-5-oligoadenylate synthetase 3 (OAS3), general transcription factor IIH subunit 4 (GTF2H4) and interferon gamma (IFNG) genes with susceptibility to precancerous lesions and cervical cancer. In total, 608 female participants, consisting of 199 patients with persistent low-grade precancerous lesions (CIN1), 100 with high-grade precancerous lesions (CIN2/3), 17 patients with cervical cancer and 292 healthy controls, were enrolled in this study. SNPs were tested for associations with each of the above-mentioned cervical group lesions or when considering an overall patient group. A significant difference for rs4737999 was observed between the controls and the overall patient group considering the recessive mode of inheritance [odds ratio (OR), 0.48; 95% confidence interval (CI), 0.24–0.96; P=0.033]. This effect was even stronger on the risk of CIN1 lesions. Carriers of the rs4737999 AA genotype were almost 3-fold less likely of having low grade lesions compared to the other genotypes. On the whole, this study provides evidence of an influence of the SULF1 gene rs4737999 SNP in the development of precancerous lesions/cervical cancer.
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Affiliation(s)
- Efthimios Dardiotis
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, 41100 Larissa, Greece
| | - Vasileios Siokas
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, 41100 Larissa, Greece
| | - Antonios Garas
- Department of Obstetrics and Gynecology, University Hospital of Larissa, 41100 Larissa, Greece
| | | | - Maria Kyrgiou
- Department of Surgery and Cancer, IRDB, Imperial College London, London W120NN, UK.,West London Gynaecological Cancer Centre, Imperial Healthcare NHS Trust, London W120HS, UK
| | - Georgia Xiromerisiou
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, 41100 Larissa, Greece
| | - Efthimios Deligeoroglou
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, 'Aretaieion' Hospital, 11528 Athens, Greece
| | - Georgios Galazios
- Department of Obstetrics/Gynecology, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Emmanuel N Kontomanolis
- Department of Obstetrics/Gynecology, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Aristidis Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Alexandros Daponte
- Department of Obstetrics and Gynecology, University Hospital of Larissa, 41100 Larissa, Greece
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Lin G, Lin KJ, Wang F, Chen TC, Yen TC, Yeh TS. Synergistic antiproliferative effects of an mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity. Dis Model Mech 2018; 11:dmm.033050. [PMID: 29666220 PMCID: PMC6124555 DOI: 10.1242/dmm.033050] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 03/26/2018] [Indexed: 12/20/2022] Open
Abstract
Although gemcitabine plus cisplatin is the gold standard chemotherapy regimen for advanced cholangiocarcinoma, the response rate has been disappointing. This study aims to investigate a novel therapeutic regimen [gemcitabine plus everolimus (rad001), an mTOR inhibitor] for cholangiocarcinoma. Gemcitabine, oxaliplatin, cetuximab and rad001 in various combinations were first evaluated in vitro using six cholangiocarcinoma cell lines. In vivo therapeutic efficacies of gemcitabine and rad001 alone and their combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model. In the in vitro study, gemcitabine plus rad001 exerted a synergistic therapeutic effect on the cholangiocarcinoma cells, irrespective of the KRAS mutation status. In the xenograft study, gemcitabine plus rad001 showed the best therapeutic effect on tumor volume change, and was associated with increased caspase-3 expression, decreased eIF4E expression, as well as overexpression of both death receptor- and mitochondrial apoptotic pathway-related genes. In a chemically induced cholangiocarcinoma-afflicted rat model, the gemcitabine plus rad001 treatment suppressed tumor glycolysis as measured by 18F-fludeoxyglucose micro-positron emission tomography. Also, increased intratumoral free choline, decreased glycerophosphocholine and nearly undetectable phosphocholine levels were demonstrated by proton nuclear magnetic resonance, supported by results of decreased choline kinase expression in western blotting. We concluded that gemcitabine plus rad001 has a synergistic antiproliferative effect on cholangiocarcinoma, irrespective of the KRAS mutation status. The antitumor effect is associated with activation of both death receptor and mitochondrial pathways, as well as the downregulation of choline kinase activity, resulting in a characteristic change in choline metabolism. Summary: Rad001 plus gemcitabine exerts a synergistic antitumor effect on cholangiocarcinoma irrespective of KRAS mutation status, with underlying mechanisms involving activation of the death receptor, mitochondrial pathways and downregulated choline kinase activity.
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Affiliation(s)
- Gigin Lin
- Department of Medical Imaging and Intervention, Imaging Core Lab, Institute for Radiological Research, Clinical Metabolomics Core Lab, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan
| | - Kun-Ju Lin
- Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan
| | - Frank Wang
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan
| | - Tse-Ching Chen
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan
| | - Tzu-Chen Yen
- Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan
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8
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Razumilava N, Lazaridis KN, Gores GJ. Cholangiocarcinoma. ZAKIM AND BOYER'S HEPATOLOGY 2018:693-707.e4. [DOI: 10.1016/b978-0-323-37591-7.00047-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers.
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Affiliation(s)
- Patrick Grierson
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Manik Amin
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
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10
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FAS c.-671A>G polymorphism and cervical cancer risk: a case-control study and meta-analysis. Cancer Genet 2017; 211:18-25. [PMID: 28279307 DOI: 10.1016/j.cancergen.2017.01.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 10/16/2016] [Accepted: 01/23/2017] [Indexed: 02/06/2023]
Abstract
This study aimed to investigate the association between FAS c.-671A>G polymorphism and cervical cancer risk in a case-control setting, followed by a meta-analysis of the published literatures. The case-control study involved genotyping of the polymorphism in 185 histopathologically confirmed cervical cancer patients and 209 cancer-free female controls utilizing PCR-RFLP technique, followed by logistic regression analyses. Meta-analysis was then conducted under homozygous, heterozygous, dominant, recessive and allele contrast models to combine data from 12 studies which consisted of 2798 cases and 3039 controls. Our case-control analysis revealed a significant association of the variant allele (G) and the homozygous variant genotype (GG) of the FAS polymorphism with an increased risk of cervical cancer. Subgroup analysis by ethnicity further confirmed the risk association in Malays (P < 0.05), but not among non-Malays (P > 0.05). However, results of meta-analysis suggested a lack of association between the polymorphism and cervical cancer risk in all the five genetic models analyzed. In conclusion, while the FAS c.-671A>G polymorphism may serve as a biomarker for cervical cancer risk prediction among the Malays, there is a limited usability of the polymorphism as a cervical cancer risk biomarker in other populations.
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11
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Goeppert B, Frauenschuh L, Zucknick M, Roessler S, Mehrabi A, Hafezi M, Stenzinger A, Warth A, Pathil A, Renner M, Schirmacher P, Weichert W. Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer. Br J Cancer 2015; 113:1343-9. [PMID: 26461054 PMCID: PMC4815783 DOI: 10.1038/bjc.2015.337] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 07/19/2015] [Accepted: 08/05/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Biliary tract cancers (BTC) are rare malignant tumours with a poor prognosis. Previously, we have presented a detailed characterisation of the inflammatory infiltrate in BTC. Here, we analysed the impact of the expression of major histocompatibility complex class I (MHC I) on patient survival and the quantity, as well as the quality of tumour-infiltrating immune cell types in BTC. METHODS MHC I expression was assessed semi-quantitatively in 334 BTC, including extrahepatic (n=129) and intrahepatic cholangiocarcinomas (n=146), as well as adenocarcinomas of the gallbladder (n=59). In addition, 71 high-grade biliary intraepithelial lesions (BilIN 3) were included. Results were correlated with data on antitumour inflammation and investigated with respect to their association with clinicopathological variables and patient survival. RESULTS BTC showed a wide spectrum of different MHC I expression patterns ranging from complete negativity in some tumours to strong homogenous expression in others. In BilIN 3, significantly higher MHC I expression levels were seen compared to invasive tumours (P=0.004). Patients with strong tumoural MHC I expression had a significantly higher overall survival probability (median survival benefit: 8 months; P=0.006). MHC I expression strongly correlated with the number of tumour-infiltrating T-lymphocytes (CD4(+) and CD8(+)) and macrophages. CONCLUSIONS Differences of MHC I expression predict patient outcome and show correlations with specific components of the inflammatory infiltrate in BTC. These findings contribute to a better understanding of immune response and immune escape phenomena in cholangiocarcinogenesis.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Lena Frauenschuh
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Manuela Zucknick
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Mohammadreza Hafezi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Arne Warth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Marcus Renner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany
| | - Wilko Weichert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg D-69120, Germany.,National Center for Tumour Diseases (NCT), Heidelberg D-69120, Germany.,Institute of Pathology, Technical University Munich D-81675, Munich, Germany.,German Cancer Consortium (DKTK)
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12
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Wiggers JK, Ruys AT, Groot Koerkamp B, Beuers U, ten Kate FJ, van Gulik TM. Differences in immunohistochemical biomarkers between intra- and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Gastroenterol Hepatol 2014; 29:1582-94. [PMID: 24787096 DOI: 10.1111/jgh.12620] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Cholangiocarcinomas of different locations differ in growth patterns, symptoms, treatment response, and survival. Still, they are regarded in many studies as a uniform malignancy. Because intra- (iCCA) and extrahepatic (eCCA) cholangiocarcinoma display such differences, we performed a systematic review and meta-analysis to analyze differences in the immunohistochemical profile of these tumors. METHODS In February 2014, we searched the two main medical literature databases MEDLINE and EMBASE. We extracted risk ratios and 95% confidence intervals from the identified studies and performed random-effects model meta-analyses in accordance with PRISMA and REMARK guidelines. RESULTS A total of 54 cohort studies, including 4458 patients and studying 102 individual markers met the inclusion criteria. Of the 57 markers that were evaluated in more than 30 iCCA and eCCA patients, 18 showed a statistically significant difference in expression between iCCA and eCCA. Biomarkers expressed differently between iCCA and eCCA included potential targets of therapy: EGFR, c-erbB-2 and VEGF-A. Several markers showed no statistical difference but large 95% confidence intervals, suggesting insufficient sample size. CONCLUSIONS This systematic review shows differences in marker expression between iCCA and eCCA. Consequently, patients with iCCA and eCCA may benefit from different treatment strategies.
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Affiliation(s)
- Jimme K Wiggers
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
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13
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FAS-670 gene polymorphism and cervical carcinogenesis risk: A meta-analysis. Biomed Rep 2014; 1:889-894. [PMID: 24649048 DOI: 10.3892/br.2013.159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 08/16/2013] [Indexed: 01/15/2023] Open
Abstract
FAS is a cell surface receptor that plays an important role in the etiology of cancer. Previous studies on the association between FAS-670 polymorphism and cervical carcinogenesis failed to reach a consensus; therefore, this meta-analysis was conducted to estimate the association of FAS-670 polymorphism and the risk of cervical cancer. This meta-analysis included 10 studies on FAS-670 genotyping, including a total of 2,901 cases and 2,831 controls. The complete overdominant model was applied in our meta-analysis [AB vs. AA: odds ratio (OR)=0.879, 95% confidence interval (CI): 0.775-0.998, P=0.046; BB vs. AA: OR=0.903, 95% CI: 0.775-1.052, P=0.190]. The random effects OR was 1.13 (95% CI: 0.95-1.34, I2=52.7%, Pheterogeneity=0.03). An ethnic subgroup analysis was subsequently performed. The OR for Asians was 1.25 (6 comparisons, 95% CI: 1.05-1.48, I2=23.5%, Pheterogeneity=0.03), whereas for Caucasians, no significant association was observed between FAS-670 polymorphism and cervical carcinogenesis (4 comparisons, OR=0.96, 95% CI: 0.75-1.24, I2=45.9%, Pheterogeneity=0.14).
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Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 2013; 109:2665-74. [PMID: 24136146 PMCID: PMC3833207 DOI: 10.1038/bjc.2013.610] [Citation(s) in RCA: 215] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 09/30/2013] [Accepted: 09/12/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Biliary tract cancers (BTC) are relatively rare malignant tumours with poor prognosis. It is known from other solid neoplasms that antitumour inflammatory response has an impact on tumour behaviour and patient outcome. The aim of this study was to provide a comprehensive characterisation of antitumour inflammatory response in human BTC. METHODS Tumour-infiltrating T lymphocytes (CD4+, CD8+, and Foxp3+), natural killer cells (perforin+), B lymphocytes (CD20+), macrophages (CD68+) as well as mast cells (CD117+) were assessed by immunohistochemistry in 375 BTC including extrahepatic (ECC; n=157), intrahepatic (ICC; n=149), and gallbladder (GBAC; n=69) adenocarcinomas. Overall and intraepithelial quantity of tumour-infiltrating immune cells was analysed. Data were correlated with clinicopathological variables and patient survival. RESULTS The most prevalent inflammatory cell type in BTC was the T lymphocyte. Components of the adaptive immune response decreased, whereas innate immune response components increased significantly in the biliary intraepithelial neoplasia - primary carcinoma - metastasis sequence. BTC patients with intraepithelial tumour-infiltrating CD4+, CD8+, and Foxp3+ T lymphocytes showed a significantly longer overall survival. Number of total intraepithelial tumour-infiltrating Foxp3+ regulatory T lymphocytes (HR: 0.492, P=0.002) and CD4+ T lymphocytes (HR: 0.595, P=0.008) were tumour grade- and UICC-stage-independent prognosticators. The subtype-specific evaluation revealed that the tumour-infiltrating lymphocytic infiltrate is a positive outcome predictor in ECC and GBAC but not in ICC. CONCLUSION Our findings characterise the immune response in cholangiocarcinogenesis and identify inflammatory cell types that influence the outcome of BTC patients. Further, we show that BTC subtypes show relevant differences with respect to density, quality of inflammation, and impact on patient survival.
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Ruys AT, Groot Koerkamp B, Wiggers JK, Klümpen HJ, ten Kate FJ, van Gulik TM. Prognostic Biomarkers in Patients with Resected Cholangiocarcinoma: A Systematic Review and Meta-analysis. Ann Surg Oncol 2013; 21:487-500. [DOI: 10.1245/s10434-013-3286-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Indexed: 12/11/2022]
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Chen X, Mo W, Peng Q, Su X. Lack of association between Fas rs180082 polymorphism and risk of cervical cancer: an update by meta-analysis. BMC MEDICAL GENETICS 2013; 14:71. [PMID: 23865866 PMCID: PMC3728080 DOI: 10.1186/1471-2350-14-71] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Accepted: 07/07/2013] [Indexed: 12/18/2022]
Abstract
Background The Fas rs180082 polymorphism has been reported to be associated with cervical cancer susceptibility, yet the results of these previous results have been inconsistent or controversial. The objective of this study was to explore whether the Fas rs180082 polymorphism confers susceptibility to cervical cancer. Methods The relevant studies were identified through a search of PubMed, Excerpta Medica Database (Embase), Elsevier Science Direct and Chinese Biomedical Literature Database (CBM) until July 2012. The association between the Fas rs180082 polymorphism and cervical cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Results A total of 7 case–control studies were eventually identified. We found no association between Fas rs180082 polymorphism and cervical cancer susceptibility in overall population (G versus A: OR = 1.03, 95% CI = 0.99-1.07, P = 0.197; AG + GG versus AA: OR = 1.04, 95% CI = 0.98-1.09, P = 0.176; GG versus AA + AG: OR = 1.04, 95% CI = 0.84–1.31, P = 0.701). In subgroup analysis, similar results were found in Asian (G versus A: OR = 1.06, 95% CI = 0.97–1.15, P = 0.195; AG + GG versus AA: OR = 1.08, 95% CI = 0.98–1.19, P = 0.176; GG versus AA + AG: OR = 0.97, 95% CI = 0.51–1.84, P = 0.935) and African (G versus A: OR = 1.01, 95% CI = 0.97-1.15, P = 0.195; AG + GG versus AA: OR = 0.99, 95% CI = 0.91–1.07, P = 0.739; GG versus AA + AG: OR = 1.09, 95% CI = 0.94–1.25, P = 0.745). Conclusion This meta-analysis has shown that there is a lack of association of the Fas rs180082 polymorphisms with cervical cancer susceptibility. However, larger scale primary studies with the consideration of gene–gene and gene–environment interactions are still required to further evaluate the interaction of Fas rs180082 polymorphism with cervical cancer susceptibility.
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Affiliation(s)
- Xu Chen
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People's Republic of China
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Zamani AG, Barlas IO, Durakbasi-Dursun G, Ural O, Erdal E, Yildirim MS. Evaluation of death pathway genesFASandFASLpolymorphisms in chronic HBV infection. Int J Immunogenet 2013; 40:482-7. [DOI: 10.1111/iji.12056] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 01/07/2013] [Accepted: 03/10/2013] [Indexed: 11/27/2022]
Affiliation(s)
- A. G. Zamani
- Medical Genetics; Meram Medical Faculty; Konya University; Konya Turkey
| | - I. O. Barlas
- Medical Biology and Genetics; Medical Faculty; Mersin University; Mersin Turkey
| | | | - O. Ural
- Infections Diseases and Clinical Microbiology; Selcuklu Medical Faculty; Selcuk University; Konya Turkey
| | - E. Erdal
- Medical Biology and Genetics; Medical Faculty; Mersin University; Mersin Turkey
| | - M. S. Yildirim
- Medical Genetics; Meram Medical Faculty; Konya University; Konya Turkey
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Sun QL, Zhang XG, Xing QT, Ding P, Feng JB, Wu XP, Wang ZM. A study of mifepristone/IFN-γ-induced apoptosis of human cholangiocarcinoma cell line FRH-0201 in vitro. Onco Targets Ther 2012. [PMID: 23180967 PMCID: PMC3497892 DOI: 10.2147/ott.s36098] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
OBJECTIVE To investigate the effects of mifepristone, a progesterone receptor (PR) antagonist, through the proliferation of human cholangiocarcinoma cell line FRH-0201 in vitro and the possible mechanisms involved. METHODS A two-step addition of poly-HRP anti-mouse immunoglobulin G detection system was used to detect the expression of PR in FRH-0201 cells. After treatments with various concentrations of mifepristone (10, 20, 40, 80, 160, and 320 μmol/L) at various time intervals (24, 48, and 72 hours), the rate of cell inhibition, the rate of cell apoptosis, and the expression of bax/bcl-2/Fas were analyzed with tetrazolium blue (MTT) assay, flow cytometry, reverse transcription polymerase chain reaction and Western blotting. The effect of mifepristone and mifepristone combined with interferon (IFN)-γ-inducing apoptosis on the cells was observed. RESULTS Mifepristone remarkably inhibited the proliferation of FRH-0201 cells, which was revealed by MTT assay in a dose- and time-dependent manner. The inhibitory rate gradually increased following the increase of the dosage of mifepristone from a low dosage (10 μmol/L) to a high dosage (320 μmol/L) at different time intervals. Flow cytometry analysis showed mifepristone increased the rate of the FRH-0201 cell-line apoptosis. Notably, the rate of apoptosis increased markedly when the cells were pretreated with IFN-γ and then treated with mifepristone. In addition, mifepristone obviously upregulated bax and Fas expression and downregulated bcl-2 expression. CONCLUSION Mifepristone effectively inhibited the growth of PR-positive human cholangiocarcinoma cell line FRH-0201 in vitro through multiple mechanisms. Mifepristone combined with IFN-γ might therefore induce the apoptosis of the cell line, which is possibly a beneficial clinical scheme for patients suffering from cholangiocarcinoma.
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Affiliation(s)
- Qi-Long Sun
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Gu FM, Gao Q, Shi GM, Zhang X, Wang J, Jiang JH, Wang XY, Shi YH, Ding ZB, Fan J, Zhou J. Intratumoral IL-17⁺ cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma. Ann Surg Oncol 2012; 19:2506-14. [PMID: 22411204 DOI: 10.1245/s10434-012-2268-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory reactions at a tumor site have both detrimental and beneficial effects on tumor progression. This study was designed to assess the clinical significance of tumor-infiltrating inflammatory cells in patients with intrahepatic cholangiocarcinoma (ICC). METHODS A total of 123 consecutive ICC patients who underwent curative resection were enrolled. Tissue microarray and immunohistochemistry were used to analyze the distribution and clinical relevance of IL-17(+), FOXP3(+), CD8(+), CD66b(+) cells, and microvessel density (CD34) in different microanatomical areas. RESULTS IL-17(+) cells, FOXP3(+) lymphocytes, CD66b(+) neutrophils, and microvessels were enriched predominantly in intratumor (IT) area, whereas CD8(+) lymphocytes were most abundant in tumor invasive front. On univariate analyses, increasing IL-17 (IT) (+) and neutrophils(IT) were significantly associated with worse patient survival. Multivariate analyses revealed that IL-17 (IT) (+) (hazard ratio [HR] = 1.59; 95% confidence interval [CI], 1.05-2.41; P = 0.028), neutrophils(IT) (HR = 1.76; 95% CI, 1.16-2.65; P = 0.007), and their combination (HR 2.8; 95% CI 1.72-4.57; P < 0.001) were independent prognostic factors, which were superior to conventional clinicopathologic features, such as intrahepatic metastasis and TNM stage. IL-17 (IT) (+) significantly correlated with the presence of lymph node metastasis, intrahepatic metastasis, and advanced stages, whereas neutrophils(IT) correlated with the presence of vascular invasion. In addition, significant positive correlations were detected among densities of IL-17(+) cells, neutrophils, and microvessel density. CONCLUSIONS Our data suggested that intratumor IL-17(+) cells, neutrophils are novel, powerful predictors of prognosis in patients with ICC.
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Affiliation(s)
- Fang-Ming Gu
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, People's Republic of China
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Tong N, Zhang L, Sheng X, Wang M, Zhang Z, Fang Y, Xue Y, Li J, Zhang Z. Functional polymorphisms in FAS, FASL and CASP8 genes and risk of childhood acute lymphoblastic leukemia: a case-control study. Leuk Lymphoma 2012; 53:1360-6. [PMID: 22211869 DOI: 10.3109/10428194.2011.654117] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Genetic polymorphisms in the promoter regions of FAS, FASL and CASP8 involved in the apoptotic signaling pathway are thought to be associated with susceptibility to cancer. We hypothesized that these functional genetic variants might be associated with the risk of childhood acute lymphoblastic leukemia (ALL). A case-control study in a Chinese population with 361 cases of ALL and 519 controls was performed to evaluate the association between FAS, FASL and CASP8 variants and risk of childhood ALL. Individuals with FAS - 1377AG had an odds ratio (OR) of 0.72 for the risk of ALL compared to - 1377GG and the variant FASL - 844CC was associated with a statistically significantly decreased risk of childhood ALL (OR = 0.38). Furthermore, combined genotypes with 5-8 protective alleles were associated with a significantly decreased risk of childhood ALL compared with those with 0-4 variants, and this decreased risk was more pronounced among the subgroups of age < 6 years, female, parental never-drinking status and never house-painting. Our results provide evidence that FAS-FASL-CASP8 polymorphisms contributed to a reduced risk of childhood ALL in our population. Larger studies are warranted to validate our findings.
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Affiliation(s)
- Na Tong
- Department of Molecular and Genetic Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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Wang W, Zheng Z, Yu W, Lin H, Cui B, Cao F. Polymorphisms of the FAS and FASL genes and risk of breast cancer. Oncol Lett 2011; 3:625-628. [PMID: 22740964 DOI: 10.3892/ol.2011.541] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 12/13/2011] [Indexed: 02/06/2023] Open
Abstract
FAS and its ligand FASL are crucial in apoptotic cell death. Loss of FAS and gain of aberrant FASL expression are common features of malignant transformation. This study was designed to investigate whether the functional polymorphisms of FAS -1377G/A (rs2234767) and FASL -844T/C (rs763110) affect the risk of developing breast cancer. Genotypes were analyzed by a polymerase chain reaction-restriction fragment length polymorphism assay in 436 breast cancer patients and 496 healthy controls. In this study, as compared to the wild-type homozygote and heterozygote, the distribution of the FAS -1377GG, GA and AA genotypes among breast cancer patients were significantly different from those among healthy controls (P=0.011), with the AA genotype being more prevalent among patients than the controls (P=0.003). Similarly, the frequencies of the FASL -844TT, TC and CC genotypes also significantly differed among breast cancer patients and healthy controls (P<0.001), with the CC genotype being significantly over-represented in breast cancer patients compared with the controls (P<0.001). In the unconditional logistic regression model following adjustment for age, the subjects carrying the FAS -1377AA genotype had a 1.75-fold increased risk [95% confidence interval (CI), 1.13-2.69] for development of breast cancer compared with patients carrying the GG genotype. Similarly, in the recessive model, the FASL -844CC genotype significantly increased the risk of breast cancer with an odds ratio (OR) of 1.92 (95% CI 1.46-2.54) compared with the TT or TT + TC genotypes. Our results suggest that functional polymorphisms in the death pathway genes FAS and FASL significantly contribute to the occurrence of breast cancer.
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Affiliation(s)
- Wenmin Wang
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang 317000, P.R. China
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Mohammadzadeh A, Pourfathollah AA, Tahoori MT, Daneshmandi S, Langroudi L, Akhlaghi M. Evaluation of apoptosis-related gene Fas (CD95) and FasL (CD178) polymorphisms in Iranian rheumatoid arthritis patients. Rheumatol Int 2011; 32:2833-6. [PMID: 21879377 DOI: 10.1007/s00296-011-2065-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Accepted: 08/10/2011] [Indexed: 11/26/2022]
Abstract
Apoptosis signals are essential for establishing homeostasis and adequate immune response. Dysregulation of apoptosis-related genes in the immune system, which could be due to gene polymorphisms, conduct to autoimmune diseases including rheumatoid arthritis. In the current study, the apoptosis-related gene Fas_-670A>G, FasL_844C>T, and FasLIVS2nt_124A>G polymorphisms were genotyped in 120 Iranian patients with rheumatoid arthritis (RA) and 112 unrelated healthy controls using PCR-RFLP method. Among the 120 RA patients being heterozygous in the promoter region of Fas_-670A/G (OR 1.42,CI 0.92-1.52, P = 0.18) and FasL_-844C/T (OR 1.42, CI 0.92-1.52, P = 0.18) and homozygous in the minor allele for FasLIVS2nt_124G/G (OR 1.43, CI 0.76-1.81, P = 0.7), the frequency of these polymorphisms is higher in the cases than in controls and the elevated risk of RA were observed when the patient compared with controls, although this is not statistically significant.
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Affiliation(s)
- Adel Mohammadzadeh
- Immunology Department, Faculty of Medical Sciences, Tarbiat Modares University, PO Box: 14155-111 Tehran, Iran
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Pan D, Yan Q, Chen Y, McDonald JM, Song Y. Trifluoperazine regulation of calmodulin binding to Fas: a computational study. Proteins 2011; 79:2543-56. [PMID: 21656570 PMCID: PMC3132223 DOI: 10.1002/prot.23081] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 04/26/2011] [Accepted: 05/04/2011] [Indexed: 12/13/2022]
Abstract
Death-inducing signaling complex (DISC) formation is a critical step in Fas-mediated signaling for apoptosis. Previous experiments have demonstrated that the calmodulin (CaM) antagonist, trifluoperazine (TFP) regulates CaM-Fas binding and affects Fas-mediated DISC formation. In this study, we investigated the anti-cooperative characteristics of TFP binding to CaM and the effect of TFP on the CaM-Fas interaction from both structural and thermodynamic perspectives using combined molecular dynamics simulations and binding free energy analyses. We studied the interactions of different numbers of TFP molecules with CaM and explored the effects of the resulting conformational changes in CaM on CaM-Fas binding. Results from these analyses showed that the number of TFP molecules bound to CaM directly influenced α-helix formation and hydrogen bond occupancy within the α-helices of CaM, contributing to the conformational and motion changes in CaM. These changes affected CaM binding to Fas, resulting in secondary structural changes in Fas and conformational and motion changes of Fas in CaM-Fas complexes, potentially perturbing the recruitment of Fas-associated death domain for DISC formation. The computational results from this study reveal the structural and molecular mechanisms that underlie the role of the CaM antagonist, TFP, in regulation of CaM-Fas binding and Fas-mediated DISC formation in a concentration-dependent manner.
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Affiliation(s)
- Di Pan
- Department of Biomedical Engineering, The University of Alabama at Birmingham, AL 35294
| | - Qi Yan
- Department of Biomedical Engineering, The University of Alabama at Birmingham, AL 35294
| | - Yabing Chen
- Department of Pathology, The University of Alabama at Birmingham, AL 35294
- VA Medical Center Birmingham, AL 35294
| | - Jay M McDonald
- Department of Pathology, The University of Alabama at Birmingham, AL 35294
- VA Medical Center Birmingham, AL 35294
| | - Yuhua Song
- Department of Biomedical Engineering, The University of Alabama at Birmingham, AL 35294
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Nunobiki O, Ueda M, Toji E, Yamamoto M, Akashi K, Sato N, Izuma S, Torii K, Tanaka I, Okamoto Y, Noda S. Genetic Polymorphism of Cancer Susceptibility Genes and HPV Infection in Cervical Carcinogenesis. PATHOLOGY RESEARCH INTERNATIONAL 2011; 2011:364069. [PMID: 21660264 PMCID: PMC3108378 DOI: 10.4061/2011/364069] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Accepted: 03/03/2011] [Indexed: 01/30/2023]
Abstract
It is widely accepted that specific human papillomavirus (HPV) types are the central etiologic agent of cervical carcinogenesis. However, a number of infected women do not develop invasive lesions, suggesting that other environmental and host factors may play decisive roles in the persistence of HPV infection and further malignant conversion of cervical epithelium. Although many previous reports have focused on HPV and environmental factors, the role of host susceptibility to cervical carcinogenesis is largely unknown. Here, we review the findings of genetic association studies in cervical carcinogenesis with special reference to polymorphisms of glutathione-S-transferase (GST) isoforms, p53 codon 72, murine double-minute 2 homolog (MDM2) gene promoter 309, and FAS gene promoter -670 together with HPV types including our recent research results.
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Affiliation(s)
- Osamu Nunobiki
- Department of Medical Technology, Kobe Tokiwa University, 6-2 2 chome, Ohtanicho, Nagataku, Hyogo, Kobe 653-0838, Japan
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Du C, Wang Y. The immunoregulatory mechanisms of carcinoma for its survival and development. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:12. [PMID: 21255410 PMCID: PMC3031251 DOI: 10.1186/1756-9966-30-12] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 01/21/2011] [Indexed: 12/24/2022]
Abstract
The immune system in patients detects and eliminates tumor cells, but tumors still progress persistently. The mechanisms by which tumor cells survive under the pressure of immune surveillance are not fully understood. This review is to present the evidence from clinical studies, showing a significant correlation of clinicopathological features of carcinoma with: (1) the loss of classical human leukocyte antigen class I, (2) the up-regulation of non-classical human leukocyte antigen class I, pro-apoptotic Fas ligand and receptor-binding cancer antigen expressed on SiSo cells I, and (3) the formation of immunosuppressive microenvironment by up-regulation of transforming growth factor-beta, Galectin-1, inhibitory ligand B7s, indoleamine 2,3-dioxygenase and arginase, as well as by recruitment of tumor-induced myeloid-derived suppressor cells and regulatory T cells. All of these factors may together protect carcinoma cells from the immune-cytotoxicity.
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Affiliation(s)
- Caigan Du
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
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Humphreys EH, Williams KT, Adams DH, Afford SC. Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent apoptosis, but are insensitive to direct activation with exogenous Fas ligand. PLoS One 2010; 5:e14037. [PMID: 21103345 PMCID: PMC2984448 DOI: 10.1371/journal.pone.0014037] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 10/18/2010] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. AIMS To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. RESULTS Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. CONCLUSIONS 1) Both primary and malignant cholangiocytes are relatively resistant to Fas-mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes.
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Affiliation(s)
- Elizabeth H. Humphreys
- Centre for Liver Research, MRC Centre for Immune Regulation, The Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Kevin T. Williams
- Centre for Liver Research, MRC Centre for Immune Regulation, The Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - David H. Adams
- Centre for Liver Research, MRC Centre for Immune Regulation, The Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Simon C. Afford
- Centre for Liver Research, MRC Centre for Immune Regulation, The Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
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Wiedmann M, Witzigmann H, Mössner J. Malignant Tumors. CLINICAL HEPATOLOGY 2010:1519-1566. [DOI: 10.1007/978-3-642-04519-6_62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yoo HJ, Yun BR, Kwon JH, Ahn HS, Seol MA, Lee MJ, Yu GR, Yu HC, Hong B, Choi K, Kim DG. Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells. Exp Mol Med 2009; 41:102-15. [PMID: 19287191 DOI: 10.3858/emm.2009.41.2.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a high mortality rate and a poor prognosis. Sarcomatous change/epithelial mesenchymal transition (EMT) of CC frequently leads to aggressive intrahepatic spread and metastasis. The aim of this study was to identify the genetic alterations and gene expression pattern that might be associated with the sarcomatous change in CC. Previously, we established 4 human CC cell lines (SCK, JCK1, Cho-CK, and Choi-CK). In the present study, we characterized a typical sarcomatoid phenotype of SCK, and classified the other cell lines according to tumor cell differentiation (a poorly differentiated JCK, a moderately differentiated Cho-CK, and a well differentiated Choi-CK cells), both morphologically and immunocytologically. We further analyzed the genetic alterations of two tumor suppressor genes (p53 and FHIT) and the expression of Fas/FasL gene, well known CC-related receptor and its ligand, in these four CC cell lines. The deletion mutation of p53 was found in the sarcomatoid SCK cells. These cells expressed much less Fas/FasL mRNAs than did the other ordinary CC cells. We further characterize the gene expression pattern that is involved in the sarcomatous progression of CC, using cDNA microarrays that contained 18,688 genes. Comparison of the expression patterns between the sarcomatoid SCK cells and the differentiated Choi-CK cells enabled us to identify 260 genes and 247 genes that were significantly over-expressed and under-expressed, respectively. Northern blotting of the 14 randomly selected genes verified the microarray data, including the differential expressions of the LGALS1, TGFBI, CES1, LDHB, UCHL1, ASPH, VDAC1, VIL2, CCND2, S100P, CALB1, MAL2, GPX1, and ANXA8 mRNAs. Immunohistochemistry also revealed in part the differential expressions of these gene proteins. These results suggest that those genetic and gene expression alterations may be relevant to the sarcomatous change/EMT in CC cells.
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Affiliation(s)
- Hee-Jung Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute for Medical Sciences, Chonbuk National University Medical School and Hospital, Jeonju 561-712, Korea
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Briggs CD, Neal CP, Mann CD, Steward WP, Manson MM, Berry DP. Prognostic molecular markers in cholangiocarcinoma: a systematic review. Eur J Cancer 2009; 45:33-47. [PMID: 18938071 DOI: 10.1016/j.ejca.2008.08.024] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2008] [Revised: 08/06/2008] [Accepted: 08/26/2008] [Indexed: 12/24/2022]
Abstract
The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.
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Affiliation(s)
- Christopher D Briggs
- Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Biocentre, University of Leicester, Leicester, United Kingdom.
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Zhang HY, Li JY, Zhang JY. Effect of Fas, FasL and Caspase-3 on apoptosis of retinoic acid-induced gastric carcinoma cells. Shijie Huaren Xiaohua Zazhi 2008; 16:3255-3260. [DOI: 10.11569/wcjd.v16.i29.3255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect on apoptosis of retinoic acid (RA)-induced BGC-803 gastric carcinoma cells and its relationship with the expression of Fas, FasL and Caspase-3.
METHODS: BGC-803 cells were treated with different concentrations of RA (0.001, 0.01, 0.1, 1, 10, 20 μmol/L) for 72 h. Then methyl-tetrazolium (MTT) assay was performed to determine the growth inhibition of BGC-803 cells; cell apoptosis rate was determined using flow cytometry; the feature of cell apoptosis was observed by Hoechst33342/PI staining; the mRNA expression of Fas, FasL and Caspase-3 were estimated using reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: After BGC-803 cells were treated with RA (0.1-20 μmol/L) for 72 h, RA inhibited the growth of cells significantly compared with that in the control group (32.61%, 44.42%, 48.14%, 51.15% vs 0.657%; all P < 0.01). Cells in G2/M were significantly increased after the cells were treated with 20 μmol/L RA for 12 h, 24 h and 48 h. G1 peak specific to apoptosis was observed and also observed were chromatic agglutination and rupture of caryon membrane. Expressions of Fas, FasL and Caspase-3 mRNA were up-regulated significantly by RA for 48 h compared with that in the control group.
CONCLUSION: Fas, FasL and Caspase-3 are involved in gastric carcinoma cell apoptosis induced by RA.
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Conformation and free energy analyses of the complex of calcium-bound calmodulin and the Fas death domain. Biophys J 2008; 95:5913-21. [PMID: 18820240 DOI: 10.1529/biophysj.108.130542] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Previous studies have demonstrated a calcium-dependent interaction of calmodulin (CaM) and Fas that is regulated during Fas-induced apoptosis in several cell lines, including cholangiocarcinoma, Jurkat cells, and osteoclasts. The binding of CaM and Fas has been identified on residues 231-254 of Fas; the V254N point mutation decreases the CaM/Fas binding, and the C-terminal deletion mutation increases the CaM/Fas binding. Recent studies have shown that CaM is recruited into the Fas-mediated death-inducing signaling complex (DISC) in a calcium-dependent manner. However, the molecular mechanisms whereby Fas mutations and CaM/Fas binding might regulate Fas-mediated DISC formation are unknown. In this study we investigated the binding thermodynamics and conformation of the CaM/Fas complexes with combined explicit solvent molecular-dynamics simulations and implicit solvent binding free-energy calculations. The binding free-energy analysis demonstrated that the Fas V254N point mutation reduced its binding affinity with CaM. In contrast, the Fas mutant with the deletion of the 15 amino acid at the C-terminus increased its binding to CaM. These observations are consistent with previous findings from biochemical studies. Conformational analyses further showed that the Fas V254N mutation resulted in an unstable conformation, whereas the C-terminal deletion mutation stabilized the Fas conformation, and both mutations resulted in changes of the degree of correlation between the motions of the residues in Fas. Analysis of the CaM/Fas complex revealed that CaM/Fas binding stabilized the conformation of both CaM and Fas and changed the degree of correlated motion of the residues of CaM and Fas. The results presented here provide structural evidence for the roles of Fas mutations and CaM/Fas binding in Fas-induced DISC formation. Understanding the molecular mechanisms of CaM/Fas binding in Fas-mediated DISC formation should provide important insights into the function of Fas mutations and CaM in regulating Fas-mediated apoptosis.
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Calmodulin binding to cellular FLICE-like inhibitory protein modulates Fas-induced signalling. Biochem J 2008; 412:459-68. [PMID: 18257744 DOI: 10.1042/bj20071507] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
We and others have demonstrated that Fas-mediated apoptosis is a potential therapeutic target for cholangiocarcinoma. Previously, we reported that CaM (calmodulin) antagonists induced apoptosis in cholangiocarcinoma cells through Fas-related mechanisms. Further, we identified a direct interaction between CaM and Fas with recruitment of CaM into the Fas-mediated DISC (death-inducing signalling complex), suggesting a novel role for CaM in Fas signalling. Therefore we characterized the interaction of CaM with proteins recruited into the Fas-mediated DISC, including FADD (Fas-associated death domain)-containing protein, caspase 8 and c-FLIP {cellular FLICE [FADD (Fas-associated death domain)-like interleukin 1beta-converting enzyme]-like inhibitory protein}. A Ca(2+)-dependent direct interaction between CaM and FLIP(L), but not FADD or caspase 8, was demonstrated. Furthermore, a 37.3+/-5.7% increase (n=6, P=0.001) in CaM-FLIP binding was observed at 30 min after Fas stimulation, which returned to the baseline after 60 min and correlated with a Fas-induced increase in intracellular Ca(2+) that reached a peak at 30 min and decreased gradually over 60 min in cholangiocarcinoma cells. A CaM antagonist, TFP (trifluoperazine), inhibited the Fas-induced increase in CaM-FLIP binding concurrent with inhibition of ERK (extracellular-signal-regulated kinase) phosphorylation, a downstream signal of FLIP. Direct binding between CaM and FLIP(L) was demonstrated using recombinant proteins, and a CaM-binding region was identified in amino acids 197-213 of FLIP(L). Compared with overexpression of wild-type FLIP(L) that resulted in decreased spontaneous as well as Fas-induced apoptosis, mutant FLIP(L) with deletion of the CaM-binding region resulted in increased spontaneous and Fas-induced apoptosis in cholangiocarcinoma cells. Understanding the biology of CaM-FLIP binding may provide new therapeutic targets for cholangiocarcinoma and possibly other cancers.
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Bowlus CL. Tumor Immunology. LIVER IMMUNOLOGY 2008:137-149. [DOI: 10.1007/978-1-59745-518-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Liu KH, Liao LM, Ro LS, Wu YL, Yeh TS. Thalidomide attenuates tumor growth and preserves fast-twitch skeletal muscle fibers in cholangiocarcinoma rats. Surgery 2007; 143:375-83. [PMID: 18291259 DOI: 10.1016/j.surg.2007.09.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2007] [Revised: 09/06/2007] [Accepted: 09/14/2007] [Indexed: 10/22/2022]
Abstract
BACKGROUND The prognosis for cholangiocarcinoma remains dismal due to a low resection rate and early recurrence. Cancer cachexia is associated with decreased survival and poor quality of life. Herein, we present a rat model of cholangiocarcinoma and demonstrate that thalidomide attenuates tumor growth and improves cachexia. METHODS A cholangiocarcinoma model was established using Sprague-Dawley rats that were fed thioacetamide for 40 weeks. Cholangiocarcinoma rats were treated using either thalidomide or saline for 8 weeks. Tumor growth and body weight were recorded for all animals. The expression of CD31, VEGF, and eIF4E of cholangiocarcinoma were determined using immunohistochemistry. Level of apoptosis and Fas-mediated apoptosis genes of cholangiocarcinoma were determined using TUNEL assay and ribonuclease protection assay, respectively. The distribution of fast-twitch soleus skeletal muscle fibers was determined as was the expression of TNFalpha and TGFbeta1 within soleus muscle. RESULTS After an 8-week treatment, the mean weight of saline- and thalidomide-treated rats was 24% and 19%, respectively, less than that of control (ANOVA, P < .05). The tumor volume (x +/-SD) of thalidomide-treated rats was less than saline-treated rats (1.9 +/- 0.4 vs 4.6 +/- 1.3 cm3, P < .01). The expression of CD31, eIF4E, and VEGF of cholangiocarcinoma was less than thalidomide-treated rats than for saline-treated rats, while the level of apoptosis of tumor cells was greater for thalidomide- treated rats than for saline-treated rats. The expression of mRNA for Fas, caspase-3, and Bax of cholangiocarcinoma in the thalidomide-treated rats was greater than for saline-treated rats. The number of fast-twitch skeletal muscle fibers per 500 mm2 of control, saline-, and thalidomide-treated rats was 43 +/- 6, 14 +/- 3, and 41 +/- 8 (ANOVA, P < .001). The expression of TNFalpha and TGFbeta1 of soleus muscles for thalidomide-treated rats was less than for saline-treated rats. CONCLUSIONS Using our rat cholangiocarcinoma model, we demonstrated that thalidomide inhibited tumor growth and was associated with a decrease in expression of reduced eIF4E and VEGF expression; in addition, thalidomide preserved fast-twitch skeletal muscle fibers and was associated with decreased expression of TNFalpha and TGFbeta1.
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Affiliation(s)
- Keng-Hao Liu
- Department of Surgery, Xiamen Chang Gung and Hospital Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan
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Lerma E, Romero M, Gallardo A, Pons C, Muñoz J, Fuentes J, Lloveras B, Catasus L, Prat J. Prognostic significance of the Fas-receptor/Fas-ligand system in cervical squamous cell carcinoma. Virchows Arch 2007; 452:65-74. [PMID: 18000680 DOI: 10.1007/s00428-007-0535-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Revised: 10/17/2007] [Accepted: 10/22/2007] [Indexed: 11/25/2022]
Abstract
We studied whether Fas-receptor (Fas-R; CD95) expression, single-nucleotide polymorphisms (SNPs) in the Fas promoter region, and/or Fas-ligand (Fas-L) production could determine individual susceptibility to cervical cancer progression. The clinicopathologic features of 38 patients with cervical squamous carcinomas (22 stage I, 8 stage II, and 8 stage III+) were reviewed and related with: (a) Fas-R expression by immunohistochemistry; (b) Fas-R SNPs at -670 and -1377 locations by restriction fragment length polymorphism and DNA sequencing; and (c) Fas-L expression by immunohistochemistry. Overall and disease-free survival curves showed significant differences in relation to stage (p < 0.001). Fas-R was identified in 20 of 38 (52.6%) tumors without statistical differences in survival, stage, or Fas-L overproduction. Fas-R GG genotype was more common than expected in advanced tumors (p = 0.065). The Fas-R-1377A allele and AA genotype were unrelated with survival, stage, or Fas-R expression. Fas-L overproduction was detected in 20 of 38 (52.6%) tumors; it was more frequent in advanced-stage tumors and was inversely related to survival (p = 0.03) and decrease in host inflammatory response (p = 0.01). Fas-R expression by tumor cells seems unrelated to stage or lymphoid infiltrate. Tumor production of Fas-L may represent an attempt to destroy the host's lymphocytic reaction.
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Affiliation(s)
- Enrique Lerma
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
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Zhang Z, Wang LE, Sturgis EM, El-Naggar AK, Hong WK, Amos CI, Spitz MR, Wei Q. Polymorphisms of FAS and FAS Ligand Genes Involved in the Death Pathway and Risk and Progression of Squamous Cell Carcinoma of the Head and Neck. Clin Cancer Res 2006; 12:5596-602. [PMID: 17000697 DOI: 10.1158/1078-0432.ccr-05-1739] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Alteration of the FAS/FAS ligand (FASLG) pathway regulating cell death may lead to cancer development, but the effects of functional promoter polymorphisms of the FAS and FASLG genes on risk of squamous cell carcinoma of the head and neck (SCCHN) are unknown. DESIGN We genotyped the FAS -1377 G>A, FAS -670 A>G, FASLG -844 C>T, and FASLG IVS2nt -124 A>G polymorphisms in 721 case patients with SCCHN and 1,234 cancer-free non-Hispanic White control subjects frequency-matched by age and sex. Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS Compared with the FAS -1377 GG and -670 AA genotypes, the FAS -1377 AA and -670 (GG+AG) genotypes were associated with an increased risk of SCCHN (OR, 2.23; 95% CI, 1.07-4.64 and OR, 1.24; 95% CI, 1.01-1.52, respectively), whereas no risk of SCCHN was associated with any of the FASLG genotypes. When we used the combined FAS -1377 (GG+AG)/-670 AA genotypes as the reference, we found that the individuals carrying the FAS -1377 AA/-670 (GG+AG) had the highest risk (OR, 2.69; 95% CI, 1.24-5.83), whereas individuals carrying genotypes other than FAS -1377 (GG+AG)/-670 AA had a higher risk of SCCHN (OR, 1.24; 95% CI, 1.01-1.52). Furthermore, the elevated risk was particularly evident for pharyngeal cancer with the larger tumors without regional lymph metastasis (OR, 1.77; 95% CI, 1.07-2.94). CONCLUSIONS The FAS (but not FASLG) polymorphisms seem to contribute to risk of developing SCCHN, particularly the pharyngeal cancer in non-Hispanic Whites. However, potential selection bias warrants future population-based studies to verify the findings.
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Affiliation(s)
- Zhengdong Zhang
- Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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Li C, Wu W, Liu J, Qian L, Li A, Yang K, Wei Q, Zhou J, Zhang Z. Functional polymorphisms in the promoter regions of the FAS and FAS ligand genes and risk of bladder cancer in south China: a case–control analysis. Pharmacogenet Genomics 2006; 16:245-51. [PMID: 16538171 DOI: 10.1097/01.fpc.0000194425.58511.a7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND FAS and FASLG together initiate apoptosis, which prevents tumor development. FAS and FASLG polymorphisms in the promoter regions can alter the transcriptional activities and thus alter risk of cancer. We hypothesized that the FAS -1377G>A, -670A>G, and FASLG -844T>C polymorphisms are associated with risk of bladder cancer. METHODS In a hospital-based case-control study of 216 case patients with newly diagnosed bladder transitional cell carcinoma and 252 cancer-free controls frequency-matched by age and sex, we genotyped polymorphisms using PCR-restriction fragment length polymorphism. RESULTS We found a statistically significantly increased risk of bladder cancer associated with the FASLG -844CC genotype [adjusted OR=1.51; 95% CI 1.03-2.23] compared with -844 (CT+TT). Consistently, the FAS haplotype genotypes with 2-4 variant (risk) alleles (-1377A and -670A) were associated with an increased risk of bladder cancer compared to 0-1 variants (OR=2.14; 95% CI 1.10-4.16). Furthermore, when we evaluated these three polymorphisms together, we found that the combined genotypes with 4-6 variant (risk) alleles (-1377A, -670A, and -844C) were associated with an increased risk of bladder cancer (OR=1.58; 95% CI 1.07-2.34) compared to 1-3 variants, and this increased risk was more pronounced among subgroups of aged >50 years (OR=1.70; 95% CI 1.11-2.61) and smokers (OR=1.88; 95% CI 1.06-3.32). CONCLUSIONS FAS and FASLG polymorphisms appear to jointly contribute to risk of bladder cancer in this southern Chinese population. Larger studies are needed to verify these findings.
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Affiliation(s)
- Chunping Li
- Department of Molecular Genetic Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
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Lai HC, Lin WY, Lin YW, Chang CC, Yu MH, Chen CC, Chu TY. Genetic polymorphisms of FAS and FASL (CD95/CD95L) genes in cervical carcinogenesis: An analysis of haplotype and gene-gene interaction. Gynecol Oncol 2005; 99:113-8. [PMID: 15996722 DOI: 10.1016/j.ygyno.2005.05.010] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2005] [Revised: 05/16/2005] [Accepted: 05/18/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Whereas human papillomavirus (HPV) infection is necessary but not sufficient for cervical carcinogenesis, host genetic variations may confer individual susceptibility. Resistance to apoptosis is a hallmark of cancer in which FAS/FAS ligand signaling plays an important role. The present study examines the hypothesis that genetic polymorphisms in FAS and FAS ligand genes, alone or in combination, are associated with cervical carcinogenesis. METHODS The genotypes of FAS -670A/G, FAS -1377G/A, and FASL -844C/T were assessed in 143 patients with high-grade squamous intraepithelial lesions (HSIL), 175 patients with invasive squamous cell carcinomas (SCC), and in age-matched controls by real-time PCR with allele-specific TaqMan probes. The status of cervical high-risk HPV infection was determined and adjusted to test the independence of genotype in the risk assessment. RESULTS The A-allele and AA-genotype frequencies of FASA -670G were significantly higher in HSIL/SCC than in controls (60% vs. 54%, P = 0.04, OR 1.26 [95% CI 1.01-1.57]; 38.0% vs. 28.6%, P = 0.02, OR 1.70 [95% CI 1.07-2.70]). No association between FAS -1377 or FASL -844 polymorphisms and HSIL/SCC could be identified. The FAS -1377A/-670A haplotype conferred a higher risk for HSIL/SCC (OR 3.05, 95% CI 1.28-7.30) than FAS -670A alone (OR 1.26, 95% CI 1.28-7.30). The interaction between FAS -670AA and FASL -844CC genotypes was associated with a risk of HSIL/SCC (OR 2.13, 95% CI 1.06-4.29) higher than that of the FAS -670AA genotype alone (OR 1.70, 95% CI 1.07-2.70). CONCLUSIONS The FAS -1377A/-670A haplotype in combination with FASL -844C is associated with cervical carcinogenesis.
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Affiliation(s)
- Hung-Cheng Lai
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, 325 Section 2 Cheng-Gung Road, Taipei 114, Taiwan, ROC
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Ueda M, Hung YC, Terai Y, Yamaguchi H, Saito J, Nunobiki O, Noda S, Ueki M. Fas gene promoter -670 polymorphism (A/G) is associated with cervical carcinogenesis. Gynecol Oncol 2005; 98:129-33. [PMID: 15894356 DOI: 10.1016/j.ygyno.2005.04.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2005] [Revised: 03/31/2005] [Accepted: 04/01/2005] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To investigate the biological significance of single nucleotide polymorphism (SNP) at Fas gene promoter in cervical carcinogenesis. METHODS SNP at -670 of Fas gene promoter (A/G) together with human papillomavirus (HPV) types were examined in a total of 279 cervical smear samples and 8 human cervical squamous carcinoma cell lines using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) techniques. RESULTS 49 patients with high-grade squamous intraepithelial lesion (HSIL) had higher frequency of high-risk HPV and GA + GG genotype than 167 with low-grade SIL (LSIL) and 63 controls. G allele frequency was also higher in HSIL than in LSIL and controls. There was an increased OR (6.00; CI, 1.32-27.37; P = 0.021) for GA + GG genotype in HSIL cases compared to controls among 96 patients with high-risk HPV. 7 of 8 cervical carcinoma cell lines also showed GA or GG genotype. CONCLUSION Fas gene promoter -670 polymorphism (A/G) may be closely associated with cervical carcinogenesis in a Japanese population.
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Affiliation(s)
- Masatsugu Ueda
- Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan.
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Jhala NC, Vickers SM, Argani P, McDonald JM. Regulators of Apoptosis in Cholangiocarcinoma. Arch Pathol Lab Med 2005; 129:481-6. [PMID: 15794670 DOI: 10.5858/2005-129-481-roaic] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Context.—Dysregulation of mediators of apoptosis is associated with carcinogenesis. For biliary duct cancers, p53 gene mutation is an important contributor to carcinogenesis. Mutations in the p53 gene affect transcription of the Fas gene, resulting in lack of Fas expression on cell membrane. It has been previously shown that cloned Fas-negative but not Fas-positive human cholangiocarcinoma cells are resistant to anti–Fas-mediated apoptosis and develop tumors in nude mice. In addition, interferon gamma induces Fas expression in Fas-negative cholangiocarcinoma cells and makes them susceptible to apoptosis. Therefore, it becomes important to characterize immunophenotypic expression of p53 and Fas in normal and neoplastic human tissues of the biliary tract to further understand the pathogenesis of the disease. To date, human studies to characterize differences in immunophenotypic expression of the Fas protein between intrahepatic and extrahepatic biliary duct cancers and in their precursor lesions have not been performed.
Objective.—To report the immunophenotypic expression of p53 and Fas expression in various stages in the development of bile duct cancers (intrahepatic and extrahepatic tumor location) and their association with tumor differentiation.
Design.—Thirty bile duct cancer samples (13 intrahepatic and 17 extrahepatic) from 18 men and 12 women who ranged in age from 44 to 77 years (mean age, 65.6 years) were retrieved from the surgical pathology files. Hematoxylin-eosin–stained slides were evaluated for the type and grade of tumor and dysplastic changes in the biliary tract epithelium. Additional slides were immunohistochemically stained with p53 and anti–Fas mouse monoclonal antibody. The pattern of Fas distribution and percentage of cells positive for p53 and Fas expression were determined.
Results.—The percentage of Fas-expressing cells is significantly (P = .01) more frequently noted in extrahepatic tumors compared with intrahepatic tumors. Furthermore, Fas expression decreased from dysplastic epithelium to cholangiocarcinoma (P = .01), and this decreasing trend continued from well to poorly differentiated tumors. Nuclear p53 expression was not identified in normal and dysplastic epithelium but was noted in 30% of carcinomas (P = .02).
Conclusion.—Fas expression is an early event in pathogenesis of bile duct cancers. Immunophenotypic expression of Fas is associated with well to moderately differentiated tumors but not with poor tumor differentiation.
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Affiliation(s)
- Nirag C Jhala
- Department of Pathology, University of Alabama at Birmingham, AL 35249, USA.
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IFN-γ regulates Fas/FasL expression in cholangio carcinoma cells. Chin J Cancer Res 2005. [DOI: 10.1007/s11670-005-0008-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Abstract
Cholangiocarcinomas are devastating cancers that are increasing in both their worldwide incidence and mortality rates. The challenges posed by these often lethal biliary tract cancers are daunting, with conventional treatment options being limited and the only hope for long-term survival being that of complete surgical resection of the tumor. Unfortunately, the vast majority of patients with cholangiocarcinoma typically seek treatment with advanced disease, and often these patients are deemed poor candidates for curative surgery. Moreover, conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival, and although photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, it is not curative. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangiocarcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome. This review focuses on potential preventive targets in cholangiocarcinogenesis, such as inducible nitric oxide synthase, cyclooxygenase-2, and altered bile acid signaling pathways. In addition, molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are described in the context of various clinical and pathological presentations. Moreover, an emphasis is placed on the importance of critical signaling pathways and postulated interactions, including those of ErbB-2, hepatocyte growth factor/Met, interleukin-6/glycoprotein130, cyclooxygenase-2, vascular endothelial growth factor, transforming growth factor-beta, MUC1 and MUC4, beta-catenin, telomerase, and Fas pathways as potential molecular therapeutic targets in cholangiocarcinoma.
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Affiliation(s)
- Alphonse E Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus, Richmond, VA 23298-0297, USA.
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Enjoji M, Yamaguchi K, Nakashima M, Ohta S, Kotoh K, Fukushima M, Kuniyoshi M, Tanaka M, Nakamuta M, Watanabe T, Nawata H. Serum levels of soluble molecules associated with evasion of immune surveillance: a study in biliary disease. Liver Int 2004; 24:330-4. [PMID: 15287856 DOI: 10.1111/j.1478-3231.2004.0931.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Biliary carcinoma cells produce the transmembrane proteins, Fas, FasL, and RCAS1. It has been demonstrated that the Fas/FasL and RCAS1 systems induce apoptosis of activated immune cells and that the soluble isoforms of these proteins (sFas, sFasL, and sRCAS1) also exhibit this function. METHODS We measured serum levels of these soluble-types in patients with biliary disease by ELISA and investigated their clinical significance. RESULTS In some cases of cholangitis and autoimmune biliary disease, serum sFasL values were over 0.1 ng/ml but the protein was undetectable in any patients with biliary carcinoma. sFas levels were significantly higher in the autoimmune disease (mean, 6.83 ng/ml) and cancer (mean, 6.42 ng/ml) groups than in the cholangitis group (mean, 4.23 ng/ml) and normal controls (mean, 2.93 ng/ml). However, the sFas values in malignancy did not correlate with the progression of clinical stage. The percentage positive for serum sRCAS1 was 9.7% in benign disease but was 63.4% in cancer. CONCLUSIONS Our data suggest that serum sFasL in biliary disease may be derived predominantly from activated immune cells and not from cancer cells and that autoimmune biliary disease may be mediated by the Fas/FasL apoptotic system. sRCAS1 is highly tumor-specific and may be of value in the diagnosis of malignancy.
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Affiliation(s)
- Munechika Enjoji
- Department of Medicine and Bioregulatory Science, School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
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Thomas CR, Merrick HW. Intraoperative radiation therapy in the multimodality approach to hepatobiliary tract cancer. Surg Oncol Clin N Am 2004; 12:979-92. [PMID: 14989128 DOI: 10.1016/s1055-3207(03)00085-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
IOERT is a reasonable option to consider in patients who have biliary tract cancers above AJCC or Bismuth stage I disease. Inherent resistance of biliary tract cancer cells to ionizing radiation would indicate that IOERT alone would not eradicate most of the tumor clonagen. EBRT (either preoperatively or postoperatively) should be used in combination with IOERT at experienced institutions that have access to both modalities. The single IOERT dose ranges are 10 to 20 Gy [55,67], whereas the EBRT dose ranges from 45 to 50 Gy in 25 to 28 fractions [67]. The most common energy level used is 8 MeV or less. In addition, IOERT port sizes of less than 6 cm in diameter, and often 4 cm or less, are recommended. Finally, intraoperative reconstruction of severely damaged blood vessels may decrease the clinical manifestation of radiation-induced injury to vessels [68].
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Affiliation(s)
- Charles R Thomas
- Department of Radiation Oncology, Division of Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, San Antonio Cancer Institute, San Antonio, TX, USA.
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Abstract
Prostate cancer is the second leading cause of cancer death in the US, largely because of the limitations of our current therapeutic options, especially once the cancer has metastasized. Investigators have long sought new therapeutic modalities such as angiogenesis inhibitors, vaccines, and gene therapy, among others. It appears that a combination approach will be required to cure the majority of malignancies. Immunotherapy for prostate cancer appears feasible and a likely therapeutic modality in the armamentarium. Unfortunately, further research in basic immunology and the interaction of the immune system with other forms of therapy is needed. Many obstacles exist in immunotherapy, including vector design, tumouricidal specificity, and tumor evasion, which will have to be overcome in order to realize the maximum therapeutic benefit from this treatment modality.
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Affiliation(s)
- Joseph M Kaminski
- Department of Radiology, Medical College of Georgia, Augusta, GA 30912, USA
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Lai HC, Sytwu HK, Sun CA, Yu MH, Yu CP, Liu HS, Chang CC, Chu TY. Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis. Int J Cancer 2003; 103:221-5. [PMID: 12455036 DOI: 10.1002/ijc.10800] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The causal role of human papillomavirus (HPV) in cervical carcinogenesis is beyond reasonable questioning. The progression from HPV infection, squamous intraepithelial lesions (SIL) to squamous cell carcinomata (SCC), however, is very uncommon and inefficient. Host genetic factors that may confer the susceptibility of disease progression are largely unknown. Apoptosis is an important fail-safe check for tumor development, in which Fas/FasL interaction contributes substantially. The purpose of our study is to test the hypothesis that an A/G polymorphism at -670 of Fas promoter with different transcriptional activity is associated with the risk for cervical neoplasia. A hospital-based case-control study was conducted, in which 104 patients of low grade SIL (LSIL), 131 high grade SIL (HSIL) and 176 SCC as well as age-matched, 1:1 controls were tested for Fas polymorphism by PCR-RFLP. HPV genotypes were determined in case groups by MY PCR-reverse line blot. The frequency of A allele was significantly (p = 0.006) higher in SCC than in control, conferring an odd ratio of 1.5 (95% CI = 1.1-2.0). The distribution of Fas (-670) genotypes also differed significantly between HSIL, SCC and each of their control (p = 0.017 and 0.03, respectively), with the A/A genotype conferring an OR of 1.3 (95% CI = 1.1-1.6) and 1.6 (95% CI = 1.0-2.5), respectively. Remarkably, the frequency of A allele and A/A genotype increased gradually in accordance with the multi-step carcinogenesis from LSIL, HSIL to SCC (p(test for trend) = 0.0066 and 0.0007, respectively). In addition, there was no difference of Fas genotypes between HPV (+) and HPV (-) cases. Fas genotypes, however, differed in LSIL infected with different HPV types (p = 0.033). The present study demonstrated an association between Fas polymorphism and cervical carcinogenesis. We deduced a possible effect of apoptosis of immune cells in this virus-induced cancer.
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Affiliation(s)
- Hung-Cheng Lai
- Graduate Institutes of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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Ahn EY, Pan G, Vickers SM, McDonald JM. IFN-gammaupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma. Int J Cancer 2002; 100:445-51. [PMID: 12115528 DOI: 10.1002/ijc.10516] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Human cholangiocarcinoma is a malignancy with no effective therapy and a poor prognosis. Previously, we demonstrated that cultured human cholangiocarcinoma cell lines heterogeneously express Fas on their surface, resulting in 2 subpopulations, Fas-high and Fas-low cells. Fas-low cells are resistant to apoptosis induced by Fas antibody and the calmodulin antagonists tamoxifen and trifluoperazine and are tumorigenic in nude mice (Pan et al., Am J Pathol 1999;155:193-203). Here, we show that IFN-gamma enhances apoptosis in both Fas-high and Fas-low cells. IFN-gamma upregulates many apoptosis-related molecules, including Fas, caspase-3, caspase-4, caspase-7, caspase-8 and Bak, in both cell lines. Pretreatment with IFN-gamma facilitated Fas-mediated caspase cleavage, cytochrome c release and Bax translocation. The ability of IFN-gamma to inhibit tumorigenesis of Fas-low cells was demonstrated in nude mice. Intratumoral injection of IFN-gamma decreased tumor volumes by 78%. These findings indicate that IFN-gamma modulates the apoptotic pathway by upregulating apoptosis-related genes. This renders tumorigenic Fas-low cholangiocarcinoma cells nontumorigenic and sensitive to Fas apoptosis, thus representing a possible therapeutic modality.
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Affiliation(s)
- Eun-Young Ahn
- Department of Pathology, University of Alabama, Birmingham, AL 35294-0007, USA
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Vickers SM, Jhala NC, Ahn EY, McDonald JM, Pan G, Bland KI. Tamoxifen (TMX)/Fas induced growth inhibition of human cholangiocarcinoma (HCC) by gamma interferon (IFN-gamma). Ann Surg 2002; 235:872-8. [PMID: 12035045 PMCID: PMC1422518 DOI: 10.1097/00000658-200206000-00016] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To evaluate the response of human cholangoicarcinoma cells to TMX treatment through the Fas pathway by pretreatment with IFN-gamma. SUMMARY BACKGROUND DATA Cholangiocarcinoma remains one of the most difficult tumors to treat in clinical medicine. Currently, there are no effective chemotherapy treatments for this disease. Surgery offers the only opportunity for a cure, with the majority of patients failing to qualify for such treatment. This study seeks to evaluate a potential new modality for treatment of this disease. METHODS Human cholangiocarcinoma cells were treated with anti Fas mab and sorted to two populations (Fas-positive and Fas-negative) by FAC analysis. In vitro individual cell populations were pretreated with IFN-gamma 250 units/mL x 18hs. The treated cells assayed for caspase 3, 7, 8, Bak, and for apoptosis with Annexin V after treatment with or without TMX. In Vivo 2 x 106 5 SK-ChA-1 Fas-negative cells were injected into nude mice for development of tumor xenografts. Mice received either no treatment or intra tumor IFN-gamma and/or intra peritoneal TMX. RESULTS More than 90% (90% +/- 3.5%) of Fas-positive and 70% (71 +/- 2.3%) of Fas-negative cells underwent apoptosis after TMX treatment when pretreated with IFN-gamma. In contrast, TMX alone and IFN-gamma alone stimulated apoptosis by only 22% (22 +/- 3%) P <.00013, and 17% (17 +/- 2%) P <.0001 in Fas-ve cells respectively. In vivo human cholangiocarcinomas xenograft growth was significantly inhibited by a combination of TMX + IFN-gamma compared to controls P <.0007. CONCLUSION TMX exposure to human cholangiocarcinoma after pretreatment with IFN-gamma allows for induction of apoptosis in vitro and significant inhibition tumor xenograft growth. The combination of these two compounds may provide novel treatment regimen for cholangiocarcinoma.
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Affiliation(s)
- Selwyn M Vickers
- Department of Surgery, The University of Alabama at Birmingham and Veterans Administration Medical Center, USA.
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Kawarada Y, Yamagiwa K, Das BC. Analysis of the relationships between clinicopathologic factors and survival time in intrahepatic cholangiocarcinoma. Am J Surg 2002; 183:679-85. [PMID: 12095601 DOI: 10.1016/s0002-9610(02)00853-x] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND This study elucidated the relationships between various clinicopathologic factors and the outcome of patients with intrahepatic cholangiocarcinoma (ICC) treated by hepatic resection. METHODS A total of 37 ICC patients were treated by hepatic resection in our department between March 1979 and March 2001. Eleven clinicopathological variables (age, sex, preoperative jaundice, operative curability, number of tumors, UICC [Union Internationale Contre le Cancer] pT factor, UICC pN factor, UICC pM factor, histological tumor type, 10-year period during which they initially examined, and adjuvant therapy) were selected for univariate and multivariate analysis to evaluate their influence on the outcome. RESULTS The actuarial 1-, 3-, and 5-year survival rates in the 37 resected cases were 54.1%, 34.0%, and 23.9%, respectively. The stage of the ICC influenced their overall survival rate. The univariate analysis revealed that curative resection (P = 0.0018), UICC pT factor (P = 0.0445), pN factor (P = 0.0029), pM factor (P = 0.0022), and histological type (P = 0.0030) were significant risk factors for survival. Multivariate analysis revealed that noncurative resection, lymph node metastasis, and less differentiated histological type were significant risk factors for poor outcome. All 6 of the 37 patients who survived more than 5 years had undergone curative resection, all of their tumors were well differentiated, and none had lymph node metastasis. CONCLUSIONS Curative surgical resection remains the only effective approach to the treatment of ICC. Extensive resection is not indicated if lymph node metastasis can be identified preoperatively or intraoperatively. Current adjuvant therapy is ineffective, and it will be necessary to assess the efficacy of new adjuvant therapy strategies or the addition of new agents in terms of the outcome of ICC.
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Affiliation(s)
- Yoshifumi Kawarada
- First Department of Surgery, Mie University School of Medicine, Tsu, Mie, Japan.
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Li ZY, Zou SQ. Fas counterattack in cholangiocarcinoma: A mechanism for immune evasion in human hilar cholangiocarcinomas. World J Gastroenterol 2001; 7:860-3. [PMID: 11854917 PMCID: PMC4695610 DOI: 10.3748/wjg.v7.i6.860] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate FasL expression in hilar cholangiocarcinoma tissues and cultured cholangiocarcinoma cells, and to assess its ability to induce apoptosis.
METHODS: We studied the expression of FasL by human hilar cholangiocaroinomas tissues by immunohistochemistry, and the QBC939 cholangiocarcinoma cell line by RT-PCR, immunohistochemistry, and Western Blot. TUNEL and flow cytometry were used to detect apoptotic cells.
RESULTS: Prevalent expression of FasL was detected in 39 resected hilar cholangiocarcinoma tissues. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumor. FasL mRNA and protein expressions in cholangiocarcinoma cells could induce Jurkat cells.
CONCLUSION: Hilar cholangiocarcinomas may elude immunological surveillance by inducing, via Fas/FasL system, the apoptosis of activated lymphocytes.
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Affiliation(s)
- Z Y Li
- Department of General Surgery of Tongji Hospital, Wuhan 430030, Hubei Province, China
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