Heterogeneous expression of GAGE, NY‐ESO‐1, MAGE‐A and SSX proteins in esophageal cancer: Implications for immunotherapy

Akçakanat, Argun; Kanda, Tatsuo; Tanabe, Tadashi; Komukai, Shintarou; Yajima, Kazuhito; Nakagawa, Satoru; Ohashi, Manabu; Hatakeyama, Katsuyoshi

doi:10.1002/ijc.21219

Cited by 32 publications

(40 citation statements)

References 17 publications

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“…For this purpose, it is essential to determine the types of cancer that express CT antigens, at what frequency, and the pattern of expression within a given tumour, including percentage of positive cells, expression levels and the subcellular localization of expression. The expression of GAGE proteins in tumours has been addressed by RT -PCR in numerous studies, but until recently no anti-GAGE antibodies were available (Luftl et al, 2004;Akcakanat et al, 2006). In this study, we have generated a panel of GAGEreactive mAbs and used these to characterize the extent of heterogeneity in GAGE expression in malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…This antibody, which recognized a 26-kDa band, similar to our anti-GAGE mAbs, was recommended only for Western blot applications by the manufacturer, but two recent studies have shown that this mAb is also suitable for immunohistochemical analysis (Luftl et al, 2004;Akcakanat et al, 2006). To compare the reactivity of this antibody with the reactivity of mAbs M2, M3 and M4, the anti-GAGE-7mAb was tested in parallel with M3 for reactivity with the panel of normal and cancer tissues by immunohistochemistry.…”

Section: Comparison Of the Reactivity Of The Anti-gage Mabs With Thatmentioning

confidence: 99%

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Restriction of GAGE protein expression to subpopulations of cancer cells is independent of genotype and may limit the use of GAGE proteins as targets for cancer immunotherapy

et al. 2006

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The GAGE cancer testis antigen gene family encodes products that can be recognized by autologous T cells, and GAGE proteins have been suggested as potential targets for cancer immunotherapy. Analysis of GAGE expression in tumours has primarily been performed at the level of gene transcription, whereas little is known about GAGE expression at the protein level. To evaluate the potential of GAGE proteins as targets for cancer-specific immunotherapy, we studied the expression of these proteins in normal and malignant cells/tissues using a novel panel of monoclonal antibodies. Immunohistochemical analysis of more than 250 cancer specimens demonstrated that GAGE proteins were frequently expressed in numerous cancer types and correlated with the expression of the cancer testis antigens MAGE-A1 and NY-ESO-1. Significant intercellular and subcellular differences in GAGE protein levels were observed, and most GAGE-positive tumours also contained cancer cells lacking GAGE expression. Studies of genetically homogenous cell lines with similar intercellular heterogeneous GAGE expression showed that GAGE expression was not associated with a specific genotype, but defined a phenotypically distinct population of cells. Surprisingly, in normal tissues we found that GAGE proteins were not restricted to testis, but were also present in a subset of oocytes of resting primordial follicles and in maturing oocytes. This is the first time that a cancer testis antigen has been reported in postfoetal oocytes. The lack of GAGE expression in a subset of cancer cells within GAGE-positive tumours has decisive implications for the development of GAGE-targeted cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Comparison Of the Reactivity Of The Anti-gage Mabs With Thatmentioning

confidence: 99%

Restriction of GAGE protein expression to subpopulations of cancer cells is independent of genotype and may limit the use of GAGE proteins as targets for cancer immunotherapy

et al. 2006

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“…Several studies have examined the expression of CT-X antigens in carcinomas of the digestive tract, either at the mRNA level by RT-PCR (23)(24)(25)(26) or, more recently, at the protein level by immunohistochemical (IHC) analysis (25,(27)(28)(29)(30). The latter is clearly more relevant clinically, either as a diagnostic marker or in predicting patients that might benefit from cancertestis antigen-based cancer vaccines, as posttranscriptional control of gene expression can lead to substantial discordance between mRNA and protein expression in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Cancer–Testis Antigen Expression in Digestive Tract Carcinomas: Frequent Expression in Esophageal Squamous Cell Carcinoma and Its Precursor Lesions

Chen

Panarelli

Piotti

et al. 2014

Cancer Immunology Research

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Cancer-testis (CT) antigens are attractive tumor antigens for cancer immunotherapy. They comprise a group of proteins normally expressed in germ cells and aberrantly activated in a variety of human cancers. The protein expression of eight cancer-testis antigens [MAGEA, NY-ESO-1, GAGE, MAGEC1 (CT7), MAGEC2 (CT10), CT45, SAGE1, and NXF2] was evaluated by immunohistochemistry in 61 esophageal carcinomas (40 adenocarcinoma and 21 squamous cell carcinoma), 50 gastric carcinomas (34 diffuse and 16 intestinal type), and 141 colorectal carcinomas. The highest frequency of expression was found in esophageal squamous cell carcinomas: Positive staining for MAGEA, CT45, CT7, SAGE1, GAGE, NXF2, NY-ESO-1, and CT10 was observed in 57%, 38%, 33%, 33%, 29%, 29%, 19%, and 14% of squamous cell carcinomas, respectively. Similar staining patterns were observed in squamous dysplasias. Expression frequencies of cancer-testis antigens were seen in 2% to 24% of gastroesophageal adenocarcinomas and were not significantly different between adenocarcinomas of the stomach versus the esophagus, or between diffuse and intestinal types of gastric adenocarcinomas. Colorectal cancers did not express NY-ESO-1, CT7, CT10, or GAGE, and only infrequently expressed SAGE1 (0.7%) MAGEA (1.4%), CT45 (3.5%), and NXF2 (8.5%). We conclude that cancer-testis antigens are frequently expressed in esophageal squamous neoplasms. Although cancer-testis antigens are generally considered to be expressed later in tumor progression, they are found in squamous dysplasias, suggesting a potential diagnostic role for cancer-testis antigens in the evaluation of premalignant squamous lesions. Cancer Immunol Res; 2(5); 480-6. Ó2013 AACR.

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“…53,54 However, CGG expression is not correlated with disease progression in other malignancies such as neuroblastoma, 34-37 melanoma 55 and esophageal cancer. 56 We observed CGG expression in newly diagnosed tumors, in tumors collected after treatment with chemotherapy (osteosarcoma samples 5, 6 and 8 in Fig. 2) and in metastases.…”

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confidence: 69%

Cancer‐germline gene expression in pediatric solid tumors using quantitative real‐time PCR

Jacobs

Brasseur

Kaa

et al. 2006

Intl Journal of Cancer

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Cancer-germline genes (CGGs) code for immunogenic antigens that are present on various human tumors but not on normal tissues. The importance of CGGs in cancer immunotherapy has led to detailed studies of their expression in a range of human tumors. We measured the levels of expression of 12 CGGs in various pediatric solid tumors to identify targets for therapeutic cancer vaccines. Quantitative real-time PCR (qPCR) was used to measure the expression of 8 MAGE genes and of genes LAGE-2/NY-ESO-1 and GAGE-1, 2, 8 in 9 osteosarcomas, 10 neuroblastomas, 12 rhabdomyosarcomas and 18 Ewing's sarcomas. Nine tumors were also examined by immunohistochemistry with monoclonal antibodies specific for the MAGE-A1, MAGE-A4 and NY-ESO-1 proteins. All osteosarcoma and 80% of neuroblastoma samples expressed several CGGs at high levels. Six of 12 rhabdomyosarcomas and 11 of 18 Ewing's sarcomas expressed at least one CGG. Immunohistochemistry data correlated well with qPCR results and showed a homogeneous protein distribution pattern in most positive tumors. No correlation was found between the levels of CGG expression in the tumors and clinicopathological parameters of the patients. Pediatric solid tumors express several CGGs, which encode antigens that could be targeted in therapeutic vaccination trials. Several CGGs of the MAGE, GAGE and LAGE families are coexpressed in a large proportion of osteosarcoma and neuroblastoma samples. Some rhabdomyosarcomas express several of these genes at high levels. Ewing's sarcomas have an overall low CGG expression. ' 2006 Wiley-Liss, Inc.Key words: cancer; pediatrics; qPCR; MAGE; NY-ESO-1 Human tumors bear antigens that can be specifically recognized by autologous T lymphocytes and antibodies.1-3 It has been shown in animal models and in clinical trials that vaccination with these tumor-specific antigens can lead to the eradication of tumors. 4,5 Over the last decade, promising new treatment modalities of induction of tumor-specific T cells have been proposed and applied. 6,7 Cancer-germline genes (CGGs) are expressed in male germline cells, not in other normal adult tissues, and in many tumors. Because male germline cells do not express HLA molecules on their surface, they do not express antigens that can be recognized by T cells. As a result, the antigens encoded by CGGs are strictly tumor-specific T cell or antibody targets. These antigens are shared by many tumors. CGGs include the MAGE, [8][9][10]12 and LAGE/NY-ESO-1 13,14 families. The MAGE gene family comprises 24 genes ranged in 3 subfamilies, MAGE-A, -B and -C. A large number of antigenic peptides encoded by the MAGE, GAGE and LAGE/NY-ESO-1 genes have been found to be presented to CD4 and CD8 lymphocytes by HLA molecules expressed at the surface of tumor cells. 15Several clinical trials in which antigens encoded by CGGs were used as vaccines have shown induction of immunological responses and, in a small number of patients, clinical responses. [16][17][18][19][20][21][22] Immunotherapy is an attractive therapeutic modality for pediat...

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Heterogeneous expression of GAGE, NY‐ESO‐1, MAGE‐A and SSX proteins in esophageal cancer: Implications for immunotherapy

Cited by 32 publications

References 17 publications

Restriction of GAGE protein expression to subpopulations of cancer cells is independent of genotype and may limit the use of GAGE proteins as targets for cancer immunotherapy

Restriction of GAGE protein expression to subpopulations of cancer cells is independent of genotype and may limit the use of GAGE proteins as targets for cancer immunotherapy

Cancer–Testis Antigen Expression in Digestive Tract Carcinomas: Frequent Expression in Esophageal Squamous Cell Carcinoma and Its Precursor Lesions

Cancer‐germline gene expression in pediatric solid tumors using quantitative real‐time PCR

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