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Mitchell G, Pollack SM, Wagner MJ. Targeting cancer testis antigens in synovial sarcoma. J Immunother Cancer 2021; 9:jitc-2020-002072. [PMID: 34083416 PMCID: PMC8183285 DOI: 10.1136/jitc-2020-002072] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2021] [Indexed: 02/02/2023] Open
Abstract
Synovial sarcoma (SS) is a rare cancer that disproportionately affects children and young adults. Cancer testis antigens (CTAs) are proteins that are expressed early in embryonic development, but generally not expressed in normal tissue. They are aberrantly expressed in many different cancer types and are an attractive therapeutic target for immunotherapies. CTAs are expressed at high levels in SS. This high level of CTA expression makes SS an ideal cancer for treatment strategies aimed at harnessing the immune system to recognize aberrant CTA expression and fight against the cancer. Pivotal clinical trials are now underway, with the potential to dramatically alter the landscape of SS management and treatment from current standards of care. In this review, we describe the rationale for targeting CTAs in SS with a focus on NY-ESO-1 and MAGE-A4, the current state of vaccine and T-cell receptor-based therapies, and consider emerging opportunities for future development.
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Affiliation(s)
| | - Seth M Pollack
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Oncology, University of Washington, Seattle, Washington, USA.,Lurie Cancer Center, Northwestern University, Chicago, Illinois, USA
| | - Michael J Wagner
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA .,Oncology, University of Washington, Seattle, Washington, USA
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Das B, Senapati S. Immunological and functional aspects of MAGEA3 cancer/testis antigen. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 125:121-147. [PMID: 33931137 DOI: 10.1016/bs.apcsb.2020.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Identification of ectopic gene activation in cancer cells serves as a basis for both gene signature-guided tumor targeting and unearthing of oncogenic mechanisms to expand the understanding of tumor biology/oncogenic process. Proteins expressed only in germ cells of testis and/or placenta (immunoprivileged organs) and in malignancies are called cancer testis antigens; they are antigenic because of the lack of antigen presentation by those specific cell types (germ cells), which limits the exposure of the proteins to the immune cells. Since the Cancer Testis Antigens (CTAs) are immunogenic and expressed in a wide variety of cancer types, CT antigens have become interesting target for immunotherapy against cancer. Among CT antigens MAGEA family is reported to have 12 members (MAGEA1 to MAGEA12). The current review highlights the studies on MAGEA3 which is a CT antigen and reported in almost all types of cancer. MAGEA3 is well tried for cancer immunotherapy. Recent advances on its functional and immunological aspect warranted much deliberation on effective therapeutic approach, thus making it a more interesting target for cancer therapy.
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Affiliation(s)
- Biswajit Das
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, Odisha, India; Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shantibhusan Senapati
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, Odisha, India.
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Zhang X, Kang C, Li N, Liu X, Zhang J, Gao F, Dai L. Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis. PeerJ 2019; 7:e6375. [PMID: 30755830 PMCID: PMC6368834 DOI: 10.7717/peerj.6375] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/31/2018] [Indexed: 02/06/2023] Open
Abstract
Background Alcohol-related hepatocellular carcinoma (HCC) was reported to be diagnosed at a later stage, but the mechanism was unknown. This study aimed to identify special key genes (SKGs) during alcohol-related HCC development and progression. Methods The mRNA data of 369 HCC patients and the clinical information were downloaded from the Cancer Genome Atlas project (TCGA). The 310 patients with certain HCC-related risk factors were included for analysis and divided into seven groups according to the risk factors. Survival analyses were applied for the HCC patients of different groups. The patients with hepatitis B virus or hepatitis C virus infection only were combined into the HCC-V group for further analysis. The differentially expressed genes (DEGs) between the HCCs with alcohol consumption only (HCC-A) and HCC-V tumors were identified through limma package in R with cutoff criteria│log2 fold change (logFC)|>1.0 and p < 0.05. The DEGs between eight alcohol-related HCCs and their paired normal livers of GSE59259 from the Gene Expression Omnibus (GEO) were identified through GEO2R (a built-in tool in GEO database) with cutoff criteria |logFC|> 2.0 and adj.p < 0.05. The intersection of the two sets of DEGs was considered SKGs which were then investigated for their specificity through comparisons between HCC-A and other four HCC groups. The SKGs were analyzed for their correlations with HCC-A stage and grade and their prognostic power for HCC-A patients. The expressional differences of the SKGs in the HCCs in whole were also investigated through Gene Expression Profiling Interactive Analysis (GEPIA). The SKGs in HCC were validated through Oncomine database analysis. Results Pathological stage is an independent prognostic factor for HCC patients. HCC-A patients were diagnosed later than HCC patients with other risk factors. Ten SKGs were identified and nine of them were confirmed for their differences in paired samples of HCC-A patients. Three (SLC22A10, CD5L, and UROC1) and four (SLC22A10, UROC1, CSAG3, and CSMD1) confirmed genes were correlated with HCC-A stage and grade, respectively. SPP2 had a lower trend in HCC-A tumors and was negatively correlated with HCC-A stage and grade. The SKGs each was differentially expressed between HCC-A and at least one of other HCC groups. CD5L was identified to be favorable prognostic factor for overall survival while CSMD1 unfavorable prognostic factor for disease-free survival for HCC-A patients and HCC patients in whole. Through Oncomine database, the dysregulations of the SKGs in HCC and their clinical significance were confirmed. Conclusion The poor prognosis of HCC-A patients might be due to their later diagnosis. The SKGs, especially the four stage-correlated genes (CD5L, SLC22A10, UROC1, and SPP2) might play important roles in HCC development, especially alcohol-related HCC development and progression. CD5L might be useful for overall survival and CSMD1 for disease-free survival predication in HCC, especially alcohol-related HCC.
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Affiliation(s)
| | | | | | - Xiaoli Liu
- Henan Province People's Hospital, Zhengzhou, China
| | | | | | - Liping Dai
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
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Esfandiary A, Ghafouri-Fard S. MAGE-A3: an immunogenic target used in clinical practice. Immunotherapy 2015; 7:683-704. [PMID: 26100270 DOI: 10.2217/imt.15.29] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Melanoma antigen family A, 3 (MAGE-A3) is a cancer-testis antigen whose expression has been demonstrated in a wide array of malignancies including melanoma, brain, breast, lung and ovarian cancer. In addition, its ability to elicit spontaneous humoral and cellular immune responses has been shown in cancer patients. As antigen-specific immune responses can be stimulated by immunization with MAGE-A3, several clinical trials have used MAGE-A3 vaccines to observe clinical responses. The frequent expressions of this antigen in various tumors and its immunogenicity in cancer patients have led to application of this antigen in cancer immunotherapy. However, the results of recent clinical trials indicate that there is a need for research in the vaccine design, adjuvant selection as well as patient selection criteria.
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Affiliation(s)
- Ali Esfandiary
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran 19857-17443, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran 19857-17443, Iran
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Abd-Elsalam EAE, Ismaeil NA. Melanoma-associated antigen genes: a new trend to predict the prognosis of breast cancer patients. Med Oncol 2014; 31:285. [PMID: 25316266 DOI: 10.1007/s12032-014-0285-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 10/06/2014] [Indexed: 11/28/2022]
Abstract
MAGE-A are normally expressed in testis and placenta. Among MAGEs, the MAGE-A subtype has been the most characterized in cancers. Our study was conducted to assess the expression of (MAGE-A1-MAGE-A6) m-RNA using MMRPs and MAGE-A12 m-RNA in blood for evaluating their clinical implications in breast cancer patients. RT-PCR was carried out to detect the expression of (MAGE-A1-MAGE-A6) m-RNA using MMRPs and MAGE-A12 m-RNA in blood. The study included 100 breast cancer cases aged 41-62 years and 100 controls aged 36-53 years. MAGE m-RNA expression was not detected in healthy donors. In breast cancer patients, the positivity of (MAGE-A1-MAGE-A6) m-RNA was 44 % (44 cases), while MAGE-A12 m-RNA was expressed in 13 % (13 cases). The gene expressions of MAGE-A1-A6 and MAGE-A12 were significantly associated with advanced TNM stages (P = 0.001 and 0.034, respectively). Simultaneous estimation of the gene expressions of MAGE-A1-A6 and MAGE-A12 can detect occult hematogenous dissemination of tumor cells and may help to monitor the effectiveness of the therapy and the development of effective immunotherapeutic strategies in breast cancer.
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Fatourou EM, Koskinas JS. Adaptive immunity in hepatocellular carcinoma: prognostic and therapeutic implications. Expert Rev Anticancer Ther 2014; 9:1499-510. [DOI: 10.1586/era.09.103] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Multiple molecular markers MAGE-1, MAGE-3 and AFP mRNAs expression nested PCR assay for sensitive and specific detection of circulating hepatoma cells: Enhanced detection of hepatocellular carcinoma. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2013. [DOI: 10.1016/j.ejmhg.2012.08.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Glazer CA, Smith IM, Bhan S, Sun W, Chang SS, Pattani KM, Westra W, Khan Z, Califano JA. The role of MAGEA2 in head and neck cancer. ACTA ACUST UNITED AC 2011; 137:286-93. [PMID: 21422315 DOI: 10.1001/archoto.2011.2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To examine the role of MAGEA2 in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). DESIGN Primary tissue microarray data and quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed that MAGEA2 is differentially overexpressed in HNSCC. Functional analyses were then performed using MAGEA2 transfections and small-interfering RNA knockdowns with subsequent anchorage-dependent growth studies and cell cycle analyses. Quantitative RT-PCR was used to evaluate expression changes in p53 downstream targets after transfection of MAGEA2 into normal upper aerodigestive cell lines. RESULTS MAGEA2 is differentially overexpressed in HNSCC. In addition, MAGEA2 promotes growth in normal oral keratinocytes, whereas knockdown of MAGEA2 in HNSCC cells decreases growth. Using the HCT116 p53 wt and null cell line system, transfection of MAGEA2 induced growth in the p53 wt cell line while providing no growth advantage in the p53 mutant cells. Subsequently, transfection of MAGEA2 induced a decrease in messenger RNA expression of the p53 downstream targets CDKN1A and BAX and decreased G1 arrest in cells allowed to remain confluent for longer than 48 hours. CONCLUSIONS These data suggest that MAGEA2 is differentially expressed in HNSCC and functions, in part, through the p53 pathway by increasing cellular proliferation and abrogating cell cycle arrest. This improved understanding of MAGEA2 function and expression patterns will potentially allow for the improved ability to use MAGEA2 for detection, surveillance, and targeted therapeutics.
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Affiliation(s)
- Chad A Glazer
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, 1550 Orleans St, Room 5N.04, Baltimore, MD 21231, USA
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MAGE-3 and MAGE-4 genes as possible markers for early detection of metastases in hepatitis C virus Egyptian patients complicated by hepatocellular carcinoma. Med Oncol 2011; 29:994-9. [PMID: 21452042 DOI: 10.1007/s12032-011-9917-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2010] [Accepted: 03/18/2011] [Indexed: 12/21/2022]
Abstract
The dissemination of hepatocellular carcinoma (HCC) cells into the circulation plays a critical role in post-operative recurrence and metastasis. Early detection of metastatic tumor cells is critical to identify HCC patients at high risk of relapse. MAGE-3 and -4 genes were evaluated by reverse transcription polymerase chain reaction for the possibility of using them as new markers for early detection of metastases in 160 chronic HCV Egyptian patients, 115 of them were complicated with HCC. The expressions of MAGE-3 and MAGE-4 mRNA in peripheral blood of patients with metastatic HCC were 36 and 52%, respectively. While the expressions of MAGE-3 and MAGE-4 mRNA in peripheral blood of patients with localized HCC were 12.5 and 15%, respectively. Moreover, at least one type of mRNA was found in the peripheral blood of 68% of the metastatic HCC patients and in 20% of the localized HCC patients. While neither the controls nor the cirrhotic patients show expression of MAGE-4 mRNA in their peripheral blood. MAGE-3 and MAGE-4 may be a promising diagnostic tool for monitoring the prognosis of HCC patients and early detection of occult hematogenous metastasis of HCC.
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Fratta E, Coral S, Covre A, Parisi G, Colizzi F, Danielli R, Nicolay HJM, Sigalotti L, Maio M. The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol Oncol 2011; 5:164-82. [PMID: 21376678 DOI: 10.1016/j.molonc.2011.02.001] [Citation(s) in RCA: 276] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Revised: 01/31/2011] [Accepted: 02/03/2011] [Indexed: 12/14/2022] Open
Abstract
Cancer testis antigens (CTA) are a large family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues except for testis and placenta. This tumor-restricted pattern of expression, together with their strong in vivo immunogenicity, identified CTA as ideal targets for tumor-specific immunotherapeutic approaches, and prompted the development of several clinical trials of CTA-based vaccine therapy. Driven by this practical clinical interest, a more detailed characterization of CTA biology has been recently undertaken. So far, at least 70 families of CTA, globally accounting for about 140 members, have been identified. Most of these CTA are expressed during spermatogenesis, but their function is still largely unknown. Epigenetic events, particularly DNA methylation, appear to be the primary mechanism regulating CTA expression in both normal and transformed cells, as well as in cancer stem cells. In view of the growing interest in CTA biology, the aim of this review is to provide the most recent information on their expression, regulation and function, together with a brief summary of the major clinical trials involving CTA as therapeutic agents. The pharmacologic modulation of CTA expression profiles on neoplastic cells by DNA hypomethylating drugs will also be discussed as a feasible approach to design new combination therapies potentially able to improve the clinical efficacy of currently adopted CTA-based immunotherapeutic regimens in cancer patients.
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Affiliation(s)
- Elisabetta Fratta
- Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Via Franco Gallini 2, 33081 Aviano, Italy
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The melanoma-associated antigen-A3, -A4 genes: relation to the risk and clinicopathological parameters in breast cancer patients. Mol Cell Biochem 2011; 351:261-8. [PMID: 21264495 DOI: 10.1007/s11010-011-0734-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2010] [Accepted: 01/10/2011] [Indexed: 12/23/2022]
Abstract
This study aimed to evaluate the clinical reliability and accuracy of two MAGE transcripts (MAGE-A3, MAGE-A4 mRNA) in the peripheral blood (PB) of patients with breast cancer (BC), and to evaluate their potential limits and utility to detect BC. We aimed also to analyze their relation to clinicopathological characteristics of the tumor. This study is a prospective, controlled, double-blinded study conducted on 100 BC women and 100 age-matched control women. There were 52 patients with localized breast mass with no evidence of nodal affection or distant metastases and 48 patients suffering from metastatic BC. MAGE-A3 and MAGE-A4 mRNA in the PB were assayed using reverse transcriptase-polymerase chain reaction (RT-PCR). None of the control women was positive for either MAGE-A3, MAGE-A4. In BC women, positivity for MAGE-A3 in PB was observed in 37 patients (37%), and MAGE-A4 positivity was observed in 11 patients (11%); with 100% specificity for both transcripts. The presence of MAGE-A3 was significantly associated with nodal status (P = 0.009), tumor size (P = 0.009), and American Joint Committee on Cancer stage (P = 0.009), whereas MAGE-A4 positivity was significantly associated with histological grade (P = 0.020). RT-PCR assays of MAGE-A3 and MAGE-A4 in the PB of BC patients may have prognostic and predictive implications, and they are promising specific tumor markers of BC.
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Detection of MAGE and SSX gene expressions by RT-nested PCR using common primers in head and neck cancer. Clin Exp Otorhinolaryngol 2008; 1:97-102. [PMID: 19434280 PMCID: PMC2671794 DOI: 10.3342/ceo.2008.1.2.97] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2008] [Accepted: 04/25/2008] [Indexed: 12/14/2022] Open
Abstract
Objectives The melanoma antigen gene (MAGE) and synovial sarcoma on X chromosome (SSX) gene families are silent in most normal adult tissues, but are expressed in a variety of malignant lesions. Therefore, detection of MAGE and SSX transcription may be useful for the diagnosis of head and neck cancers. The aim of this study is to detect MAGE and SSX gene transcripts of head and neck cancers using the MAGE 1-6 assay and the SSX 1-9 assay. Methods The transcripts of MAGE 1-6 and SSX 1-9 genes were detected by the MAGE 1-6 assay and the SSX 1-9 assay respectively, in cancer cell lines, cancer tissue, and induced sputum specimens from head and neck cancer patients. Results The transcripts of MAGE 1-6 and SSX 1-9 genes were detected in 82.8% and 75.9% of head and neck cancer tissues (N=29) respectively, and 96.6% of cancer tissues expressed at least one of MAGE 1-6 or SSX 1-9 genes. In the induced sputum of head and neck cancer patients (N=18), the transcripts of MAGE 1-6 and SSX 1-9 genes were detected in 72.2% and 77.8%, respectively, and 94.4% of the sputum specimens were positive for either the MAGE 1-6 or the SSX 1-9 assay. Conclusion These results suggest that the combination of MAGE 1-6 and SSX 1-9 assays may be useful in the diagnosis of head and neck cancer.
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Ries J, Vairaktaris E, Mollaoglu N, Wiltfang J, Neukam FW, Nkenke E. Expression of melanoma-associated antigens in oral squamous cell carcinoma. J Oral Pathol Med 2008; 37:88-93. [PMID: 18197853 DOI: 10.1111/j.1600-0714.2007.00600.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Melanoma-associated antigens-A (MAGE-A) are expressed in a variety of tumors but not in normal tissues. Thus, their detection is highly specific to cancer cells, which makes them potential targets for the diagnosis, prognosis and also immunotherapy of neoplastic diseases. METHODS To determine the expression pattern and potential role of MAGE-A antigens in oral squamous cell carcinoma (OSCC), expression patterns of MAGE-A1-A6 and A12 were analyzed in 55 OSCC and 20 healthy oral mucosa using high-sensitive reverse transcription-nested polymerase chain reaction (RT-nPCR). RESULTS The 85.45% of tumor specimens expressed at least one of these genes. A significant correlation between the expression of MAGE-A1-A6 and A12 and malignancy was ascertained (P = 0.0001). On the contrary, none of the normal mucosal specimens expressed one of the MAGE-A subtypes. Antigen expression did not correlate with clinicopathological parameters, such as TNM classification, grading and clinical stage of OSCC. CONCLUSIONS Multiple simultaneous detection of MAGE-A1-A6 and A12 expression has been found to be more specific and sensitive than the detection of single MAGE-A antigen for the diagnostic and prognostic evaluation of OSCC. In addition, monitoring the expression of several MAGE-A subtypes may determine suitable immunotherapeutic targets. Subsequently, coexpressed genes may be warranted for developing polyvalent vaccines.
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Affiliation(s)
- Jutta Ries
- Department of Oral and Cranio-Maxillofacial Surgery, Friedrich-Alexander University of Erlangen/Nuremberg, Erlangen, Germany.
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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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Affiliation(s)
- Tim F Greten
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Germany.
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Kwon S, Kang SH, Ro J, Jeon CH, Park JW, Lee ES. The melanoma antigen gene as a surveillance marker for the detection of circulating tumor cells in patients with breast carcinoma. Cancer 2005; 104:251-6. [PMID: 15937912 DOI: 10.1002/cncr.21162] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Circulating occult tumors cells could be used for the surveillance of metastases after primary breast carcinoma therapy, but their detection is limited by the lack of specific molecular markers. Melanoma antigen genes (MAGEs), which are expressed in malignant tissues but not in normal tissues (except for placenta and testis), might provide such a marker. To date, however, the use of MAGEs in the detection of occult tumor cells using reverse transcription-polymerase chain reaction (RT-PCR) has been limited because of the heterogeneity and low expression of individual MAGEs in tumor tissues. METHODS We developed multiple MAGE-recognizing primers (MMRPs) that were capable of binding to the cyclic DNA of 6 MAGE-A gene subtypes (MAGE-A1-MAGE-A6). We assessed the ability of the MMRPs to detect the expression of MAGE-A gene subtypes in peripheral blood obtained from patients with benign or malignant breast disease. RESULTS MAGE-A gene expression was not detected in 32 patients with benign disease but was detected in 1 of 31 patients (3%) patients with negative lymph node breast carcinoma, in 10 of 52 patients (19%) with 1-3 positive lymph nodes, in 11 of 53 patients (21%) with > or = 4 positive lymph nodes, and in 20 of 52 patients (39%) with metastatic disease. The results were statistically significant (P < 0.0001; chi-square test for linear-by-linear association). The results also showed that the detection of MAGE-A gene expression in the blood predicted tumor progression or recurrence. CONCLUSIONS The results suggested that MAGE-A gene expression may be used for the surveillance of circulating breast carcinoma cells after primary therapy by RT-nested PCR using MMRPs.
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Affiliation(s)
- Soim Kwon
- Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, South Korea
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Xiao J, Chen HS, Fei R, Cong X, Wang LP, Wang Y, Jiang D, Wei L, Wang Y. Expression of MAGE-A1 mRNA is associated with gene hypomethylation in hepatocarcinoma cell lines. J Gastroenterol 2005; 40:716-21. [PMID: 16082588 DOI: 10.1007/s00535-005-1615-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2004] [Accepted: 03/15/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND A correlation between melanoma-associated antigen (MAGE) A1 mRNA expression and genome-wide hypomethylation has been observed in some carcinomas, but this relationship is not known in hepatocarcinoma. METHODS Total RNA and genomic DNA were prepared from ten human hepatocarcinoma cell lines in which the genetic characteristics are stable. MAGE-1 mRNA expression was determined by reverse transcription polymerase chain reaction (RT-PCR), and the level of genome-wide demethylation was evaluated by enzyme digestion and Southern-blot assay. The methylation status of the MAGE-A1 gene promoter was measured by enzyme digestion and PCR. RESULTS MAGE-A1 mRNA was detected in the hepatocarcinoma cell lines QGY-7703, SMMC-7721, HLE, BEL-7402, BEL-7404, and BEL-7405, which showed moderate to low levels of cell differentiation. In contrast, MAGE-A1 mRNA expression was not detected in the hepatoma cell lines HepG2215, HepG2, QGY-7701, and Huh7, which showed moderate to high levels of differentiation. The level of demethylation in MAGE-A1 mRNA-positive cell lines was much higher than that in MAGE-A1 mRNA-negative cell lines (P=0.02). CONCLUSIONS The results suggest that MAGE-A1 mRNA expression in human hepatoma cell lines is associated with hypomethylation of the genome and the MAGE-A1 promoter domain. This study will be helpful to reveal the expression mechanisms of MAGE-like tumor antigens in cancer cells.
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Affiliation(s)
- Jiang Xiao
- Hepatology Institute, Peking University Health Science Center People's Hospital, Beijing, 100044, China
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Shang XY, Chen HS, Zhang HG, Pang XW, Qiao H, Peng JR, Qin LL, Fei R, Mei MH, Leng XS, Gnjatic S, Ritter G, Simpson AJG, Old LJ, Chen WF. The spontaneous CD8+ T-cell response to HLA-A2-restricted NY-ESO-1b peptide in hepatocellular carcinoma patients. Clin Cancer Res 2005; 10:6946-55. [PMID: 15501973 DOI: 10.1158/1078-0432.ccr-04-0502] [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] [Indexed: 12/30/2022]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) can express various cancer-testis antigens including NY-ESO-1, members of the SSX family, members of the MAGE family, SCP-1, and CTP11. Immunotherapy directed against these antigens is a potential alternative treatment for HCC. To date, it remains unclear whether HCC patients have spontaneous immune responses to these tumor antigens. The objectives of this study were to measure immune responses to NY-ESO-1, a promising cancer vaccine candidate, in HCC patients using the HLA-A2-restricted NY-ESO-1b peptide (p157-165) to measure cellular responses and whole protein to measure antibody responses. EXPERIMENTAL DESIGN In HLA-A2(+) patients with NY-ESO-1(+) HCC, we analyzed T-cell antigen-dependent interferon (IFN)-gamma and/or Granzyme B release by enzyme-linked immunospot (ELISPOT) assay and IFN-gamma-producing intracellular cytokine flow cytometry (CytoSpot). As an assay independent of T-cell function, we performed tetramer staining. Antibodies to whole NY-ESO-1 were assayed by enzyme-linked immunosorbent assay. RESULTS The frequency of specific CD8(+) T-cell responses to NY-ESO-1b in 28 NY-ESO-1 mRNA(+)HLA-A2(+) HCC patients was 35.7% (10 of 28). The average magnitude of effector CD8(+) T cells was 0.3% (89 +/- 59 per 2.5 x 10(4) CD8(+) cells) and 1.2% as measured by IFN-gamma release ELISPOT and CytoSpot assays, respectively. These in vitro induced NY-ESO-1b-specific CD8(+) T cells can also recognize HepG2 cells transfected with pcDNA3.1-NY-ESO-1 in both IFN-gamma and Granzyme B ELISPOT assays. Frequencies of NY-ESO-1b-specific T cells in several patients were confirmed by tetramer staining. Nonfunctional tetramer(+)CD8(+) T cells were also present. The CD8(+) T-cell response was apparently increased in patients with late-stage HCC. A discordance between antibody and CD8(+) T-cell responses in HCC patients was observed. CONCLUSIONS The elevated frequency of specific CD8(+) T-cell responses to NY-ESO-1b in NY-ESO-1 mRNA(+)HLA-A2(+) HCC patients suggests that NY-ESO-1 is appropriate for use in the immunotherapy of HCC patients.
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Affiliation(s)
- Xiao-Ying Shang
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
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19
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Liu G, Ying H, Zeng G, Wheeler CJ, Black KL, Yu JS. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 2004; 64:4980-6. [PMID: 15256472 DOI: 10.1158/0008-5472.can-03-3504] [Citation(s) in RCA: 150] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
It has recently been demonstrated that malignant glioma cells express certain known tumor-associated antigens, such as HER-2, gp100, and MAGE-1. To further determine the possible utilization of these antigens for glioma immunotherapy and as surrogate markers for specific tumor antigen cytotoxicity, we characterized the presence of mRNA and protein expression in 43 primary glioblastoma multiforme (GBM) cell lines and 7 established human GBM cell lines. HER-2, gp100, and MAGE-1 mRNA expression was detected in 81.4%, 46.5%, and 39.5% of the GBM primary cell lines, respectively. Using immunoreactive staining analysis by flow cytometry, HER-2, gp100, and MAGE-1 protein expression was detected in 76%, 45%, and 38% of the GBM primary cell lines, respectively. HLA-A1-restricted epitope specific for MAGE-1 peptide (EADPTGHSY) CTL clone B07 and HLA-A2-restricted epitope specific for HER-2 peptide (KIFGSLAFL) CTL clone A05 and gp100 peptide (ITDQVPFSV) CTL clone CK3H6 were used in this study. The specificity of CTL clone was verified by HLA/peptide tetramer staining. Three CTL clones could efficiently recognize GBM tumor cells in an antigen-specific and MHC class I-restricted manner. IFN-gamma treatment can dramatically increase MHC class I expression of GBM tumor cells and significantly increase CTL recognition of tumor cells. Treatment with the DNA hypomethylating agent 5-aza-2'-deoxycytidine induced and up-regulated the mRNA expression of MAGE-1 and epitope presentation by autologous MHC. These data indicate that HER-2, gp100, and MAGE-1 could be used as tumor antigen targets for surrogate assays for antigen-specific CTLs or to develop antigen-specific active immunotherapy strategies for glioma patients.
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MESH Headings
- Animals
- Antigen Presentation
- Antigens, Neoplasm
- Azacitidine/analogs & derivatives
- Azacitidine/immunology
- Azacitidine/pharmacology
- Brain Neoplasms/genetics
- Brain Neoplasms/immunology
- Brain Neoplasms/metabolism
- COS Cells
- Cell Line, Tumor
- Chlorocebus aethiops
- DNA Methylation
- Decitabine
- Epitopes, T-Lymphocyte/immunology
- Gene Expression Regulation, Neoplastic/drug effects
- Glioblastoma/genetics
- Glioblastoma/immunology
- Glioblastoma/metabolism
- Humans
- Interferon-gamma/immunology
- Interferon-gamma/pharmacology
- Melanoma-Specific Antigens
- Membrane Glycoproteins/biosynthesis
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/immunology
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Receptor, ErbB-2/biosynthesis
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/immunology
- T-Lymphocytes, Cytotoxic/immunology
- gp100 Melanoma Antigen
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Affiliation(s)
- Gentao Liu
- Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800E, Los Angeles, CA 90048, USA
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20
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21
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Zerbini A, Pilli M, Soliani P, Ziegler S, Pelosi G, Orlandini A, Cavallo C, Uggeri J, Scandroglio R, Crafa P, Spagnoli GC, Ferrari C, Missale G. Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8+cells in patients with hepatocellular carcinoma. J Hepatol 2004; 40:102-9. [PMID: 14672620 DOI: 10.1016/s0168-8278(03)00484-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND/AIMS Members of the melanoma antigen encoding gene family are expressed in tumors of different histological types but not in normal tissue. For this reason, they are attractive targets for cancer immunotherapy. METHODS In the present study, we analyzed the expression of MAGE-1 and -3 genes in the hepatocellular carcinoma (HCC) tissue as well as frequency, phenotype and function of circulating and tumor infiltrating CD8+ cells specific for HLA-A1 and -A2 restricted epitopes of MAGE-1 and -3. RESULTS Our study shows for the first time the presence of MAGE/tetramer+ CD8 cells in the tumor tissue of patients with HCC. These cells are able to recognize the MAGE-1 sequence 161-169 and the MAGE-3 sequence 271-279. In a patient with a particularly high frequency of MAGE-1 sequence 161-169-specific T cells, phenotypic and functional analysis was performed showing a phenotype of recently-primed CD8 cells (CD28+CD27+CD45RA-CCR7). CONCLUSIONS The observation of a spontaneous in vivo priming of a MAGE-specific T cell response in patients with HCC and the high frequency of MAGE antigens expression in this tumor, makes this antigen a potential candidate for a MAGE-specific immunotherapy in hepatocellular carcinoma.
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Affiliation(s)
- Alessandro Zerbini
- Divisione Malattie Infettive ed Epatologia, Azienda Ospedaliera Universitaria di Parma, Via Gramsci 14, 43100 Parma, Italy
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22
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Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ, Itoh K, Fujita J. MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J Biol Chem 2003; 278:10668-74. [PMID: 12525503 DOI: 10.1074/jbc.m206104200] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma ranks among the most common malignancies in Southeast Asia and South Africa. Although there are many modalities of treatment, the recurrence and metastasis rates are high, and the prognosis is unsatisfactory. Gankyrin, a recently found oncoprotein, is a promising target for drug therapy because it is overexpressed in all studied hepatocellular carcinomas. Gankyrin contains six ankyrin repeats and interacts with Rb, Cdk4, and the S6 ATPase of the 26 S proteasome. In this study, a yeast two-hybrid screen with gankyrin has identified MAGE-A4 as another interacting protein. The interaction, mediated by the C-terminal half of MAGE-A4, was reproduced in mammalian cells. The interaction was specific to MAGE-A4, because other MAGE family proteins structurally similar to MAGE-A4, i.e. MAGE-A1, MAGE-A2, and MAGE-A12, did not bind to gankyrin. MAGE-A4 partially suppressed both anchorage-independent growth in vitro and tumor formation in athymic mice of gankyrin-overexpressing cells. The ability of mutant MAGE-A4 to interact with gankyrin correlated with the ability to suppress the anchorage-independent growth. These results demonstrate that MAGE-A4 binds to gankyrin and suppresses its oncogenic activity. So far, the major focus of studies on the MAGE proteins has been on their potential for cancer immunotherapy. Our results may also shed light on novel functions for MAGE-A proteins.
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Affiliation(s)
- Toshikazu Nagao
- Department of Clinical Molecular Biology, Faculty of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Japan
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23
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Zhang Y, Stroobant V, Russo V, Boon T, van der Bruggen P. A MAGE-A4 peptide presented by HLA-B37 is recognized on human tumors by cytolytic T lymphocytes. TISSUE ANTIGENS 2002; 60:365-71. [PMID: 12492812 DOI: 10.1034/j.1399-0039.2002.600503.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
'Cancer-germline' genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific antigens, which have been used in therapeutic vaccination trials of cancer patients. MAGE-A4 is expressed in more than 50% of carcinomas of esophagus, head and neck, lung, and bladder. We report here the identification of a new MAGE-A4 encoded peptide, which is recognized by a cytolytic T lymphocyte (CTL) clone on HLA-B*3701. The sequence of the peptide is SESLKMIF. It corresponds to the MAGE-A4156-163 protein sequence. When tumor cells expressing MAGE-A4 were transfected with HLA-B*3701, they were recognized by the CTL clone, demonstrating that the peptide ought to be processed in tumor cells and could therefore serve as a target for therapeutic antitumoral vaccination.
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Affiliation(s)
- Y Zhang
- Ludwig Institute for Cancer Research, 74 Avenue Hippocrate, UCL 74.59, Brussels, Belgium
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24
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Park JW, Kwon TK, Kim IH, Sohn SS, Kim YS, Kim CI, Bae OS, Lee KS, Lee KD, Lee CS, Chang HK, Choe BK, Ahn SY, Jeon CH. A new strategy for the diagnosis of MAGE-expressing cancers. J Immunol Methods 2002; 266:79-86. [PMID: 12133624 DOI: 10.1016/s0022-1759(02)00105-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The expression of melanoma antigen gene (MAGE), coding for tumor antigens recognized by cytotoxic T cell, is highly specific to cancer cells, but their use in the detection of a few cancer cells by reverse transcription-polymerase chain reaction (RT-PCR) has been limited by the low frequency of expression of individual MAGE genes. In order to increase MAGE detection rate in RT-PCR assay, here, we designed multiple MAGEs recognizing primers (MMRPs) that can bind to the sequences of cDNA of MAGE-1, -2, -3, -4a, -4b, -5a, -5b and-6 (MAGE 1-6) together. The nested RT-PCR assay using MMRPs, MAGE 1-6 assay, detected MAGE messages of 1 to 5 SNU484 cells in a background of 10(7) SNU638 cells. MAGE detection rate of MAGE 1-6 assay in cancers was higher than that of nested RT-PCR that detects single MAGE gene expression. The expressions of MAGE genes was detected by MAGE 1-6 assay in 70.4% (19/27) of head and neck cancer tissues, 91.7% (11/12) of breast cancer tissues, 75% (9/12) of lung cancer tissues. However, they were not detected in 18 benign lesions and 20 normal head and neck tissues and 30 blood samples from healthy donor. In conclusions, MAGE 1-6 assay can detect any cancer cells that express at least one of eight MAGE subtype genes, and this method may be very useful for the diagnosis of MAGE-expressing cancers.
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Affiliation(s)
- Jong Wook Park
- The Institute of Medical Science, Keimyung University School of Medicine, iC&G Co., Taegu, South Korea
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25
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Mou DC, Cai SL, Peng JR, Wang Y, Chen HS, Pang XW, Leng XS, Chen WF. Evaluation of MAGE-1 and MAGE-3 as tumour-specific markers to detect blood dissemination of hepatocellular carcinoma cells. Br J Cancer 2002; 86:110-6. [PMID: 11857021 PMCID: PMC2746529 DOI: 10.1038/sj.bjc.6600016] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2001] [Revised: 10/23/2001] [Accepted: 10/24/2001] [Indexed: 02/07/2023] Open
Abstract
The members of MAGE gene family are highly expressed in human hepatocellular carcinoma (HCC). In the present study, we tested the tumour-specific MAGE-1 and MAGE-3 transcripts in the peripheral blood of HCC patients by nested RT-PCR to detect the circulating tumour cells and evaluate their potential clinical implication. Of 30 HCC patients, the positive rate of MAGE-1 and MAGE-3 transcripts was 43.3% (13 out of 30) and 33.3% (10 out of 30) in PBMC samples, whilst the positive rate was 70% (21 out of 30) and 53.3% (16 out of 30) in the resected HCC tissue samples, respectively. The positivity for at least one MAGE gene transcript was 63.3% (19 out of 30) in PBMC samples of HCC patients and 83.3% (25 out of 30) in the resected HCC tissue samples. MAGE-1 and/or MAGE-3 mRNA were not detected in the PBMC of those patients from whom the resected HCC tissues were MAGE-1 or MAGE-3 mRNA negative, nor in the 25 PBMC samples from healthy donors. The detection of MAGE transcripts in PBMC was correlated with the advanced stages and tumour size of the HCC, being 82.4% (14 out of 17) in tumour stages III and IVa, 56.6% (five out of nine) in stage II, and null (nought out of four) in stage I. The serum alpha-FP in 33.3% (10 out of 30) of HCC patients was normal or slightly elevated (< 40 ng ml(-1)). However, six of these 10 patients (alpha-FP < 40 ng ml(-1)) were MAGE-1 and /or MAGE-3 mRNA positive in their PBMC. The follow-up survey of MAGE mRNA in PBMC was performed in 12 patients. Seven patients with persistent MAGE-1 and/or MAGE-3 mRNA positive or from negative turned to positive died because of metastasis and/or recurrence. In striking contrast, all four patients with MAGE-1 and/or MAGE-3 mRNA from positive turned to negative and one patient with persistent MAGE-3 transcript negative are alive after last test. Collectively, detection of MAGE transcripts with follow-up survey in PBMC is a feasible and reliable assay for the early prediction of the relapse and prognosis of the HCC patients.
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Affiliation(s)
- D-C Mou
- Center of Hepatobiliary Surgery, People's Hospital, Peking University Health Science Center, 42 Beilishilu, Beijing 100044, China
| | - S-L Cai
- Center of Hepatobiliary Surgery, People's Hospital, Peking University Health Science Center, 42 Beilishilu, Beijing 100044, China
| | - J-R Peng
- Center of Hepatobiliary Surgery, People's Hospital, Peking University Health Science Center, 42 Beilishilu, Beijing 100044, China
| | - Y Wang
- Institute of Hepatology, People's Hospital, Peking University Health Science Center, 42 Beilishilu, Beijing 100044, China
| | - H-S Chen
- Institute of Hepatology, People's Hospital, Peking University Health Science Center, 42 Beilishilu, Beijing 100044, China
| | - X-W Pang
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing 100083, China
| | - X-S Leng
- Center of Hepatobiliary Surgery, People's Hospital, Peking University Health Science Center, 42 Beilishilu, Beijing 100044, China
| | - W-F Chen
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing 100083, China
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Tang ZY. Hepatocellular carcinoma--cause, treatment and metastasis. World J Gastroenterol 2001; 7:445-54. [PMID: 11819809 PMCID: PMC4688653 DOI: 10.3748/wjg.v7.i4.445] [Citation(s) in RCA: 303] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2001] [Revised: 07/20/2001] [Accepted: 07/27/2001] [Indexed: 02/06/2023] Open
Abstract
In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Down-staging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved. Different modes of regional cancer therapy for HCC have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising. Biotherapy, such as cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progression as well as targets for intervention.
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Affiliation(s)
- Z Y Tang
- Liver Cancer Institute of Fudan University, 136 Yixueyuan Road, Zhongshan Hospital, Shanghai 200032, China.
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27
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Chen CH, Chen GJ, Lee HS, Huang GT, Yang PM, Tsai LJ, Chen DS, Sheu JC. Expressions of cancer-testis antigens in human hepatocellular carcinomas. Cancer Lett 2001; 164:189-95. [PMID: 11179834 DOI: 10.1016/s0304-3835(01)00379-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Though regular sonographic examination can early detect small hepatocellular carcinoma, the therapeutic results remains unsatisfactory. Antigen-specific immunotherapy is an alternative approach for controlling tumors. The prerequisite for antigen-specific cancer immunotherapy is the identification of appropriate tumor antigens. Recently, a new category of tumor-specific shared antigens, called cancer-testis antigens, has been identified. The cancer-testis antigens have been found in a variety of cancers. However, the expression of cancer-testis antigens in human hepatocellular carcinomas is unknown. The aim of this current study is to investigate the expression of cancer-testis antigens in human hepatocellular carcinomas. Reverse-transcription polymerase chain reaction (RT-PCR) was used to investigate the expression of the SSX-1,-2,-4,-5, SCP-1, NY-ESO-1 genes in tumorous and corresponding non-tumorous liver tissues. In the 30 hepatocellular carcinomas studied, SSX-1,-2,-4,-5, SCP-1, and NY-ESO-1 mRNA expressions were detected in 24 (80%), 14 (46.7%), 22 (73.3%), 10 (33.3%), 2 (6.7%), and 11 (36.7%), respectively. Expressions of these genes were detected in few non-tumor liver tissues. The cancer-testis antigens are expressed in a high percentage of hepatocellular carcinomas. These cancer-testis antigen gene products are potential targets for antigen-specific immunotherapy of hepatocellular carcinoma.
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Affiliation(s)
- C H Chen
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan
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28
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Molecular Strategy for Detecting Metastatic Cancers with Use of Multiple Tumor-specific MAGE-A Genes. Clin Chem 2001. [DOI: 10.1093/clinchem/47.3.505] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Abstract
Background: The human melanoma-associated antigen family A (MAGE-A) has high specificity and expression in various malignancies, but individual family members are expressed at low frequency in any one particular type of cancer. We therefore developed a method to detect mRNAs from multiple MAGE-A genes in a single reaction.
Methods: Universal MAGE-A (uMAGE-A) primers and probe were designed to reverse-transcribe, amplify, and detect by electrochemiluminescence (ECL) MAGE-A mRNAs on the Origen Analyzer. The assay was performed on total RNA of melanoma (n = 9 cell lines and 24 tumors), breast cancer (n = 7 and 26), and colorectal cancer (CRC; n = 5 and 12). We also evaluated blood from melanoma (n = 50), breast cancer (n = 16), and CRC (n = 21) patients.
Results: The uMAGE-A mRNA was detectable in 0.01–1 ng of cell line RNA. The identity of the uMAGE-A cDNA products was confirmed by sequencing and polyacrylamide gel electrophoresis. The uMAGE-A assay increased detection of melanoma, breast cancer, and CRC tumor by 13%, 31%, and 25%, respectively, compared with a MAGE-A1 assay, and by 17%, 19%, and 25%, respectively, compared with a MAGE-A3 assay. The uMAGE-A assay detected circulating tumor cells in the blood of melanoma (24%), breast cancer (25%), and CRC (29%) patients.
Conclusions: The uMAGE-A reverse transcription-PCR/ECL assay provides a practical and sensitive approach for detection of various metastatic cancers in tissues and blood.
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