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

Gjerstorff, Morten F.; Johansen, Lykke; Nielsen, Ole; Kock, Kirsten; Ditzel, Henrik J.

doi:10.1038/sj.bjc.6603163

Cited by 53 publications

(73 citation statements)

References 37 publications

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“…GAGE proteins were localized to both cytoplasm and nucleus, similar to the subcellular localization in spermatogonia of adult testis (Gjerstorff et al, 2006). GAGE expression was found to persist in 11% of primordial follicles of the neonatal ovary, and we previously observed GAGE expression in 30% of adult oocytes (Gjerstorff et al, 2006). The prolonged expression of GAGE in germ cells, e.g.…”

Section: Discussionmentioning

confidence: 84%

“…Moreover, MAGE-A2 was observed to down-regulate p53 transactivation by recruiting histone deacetylase 3 (Monte et al, 2006). GAGE proteins have been shown to localize to the nucleus of a subset of spermatogonia and cancer cells, indicating that GAGE may also be a regulator of gene expression (Gjerstorff et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Microwave boiling in T-EG buffer for 15 min proved to be the optimal antigen retrieval method for anti-GAGE, anti-MAGE-A1 and anti-NY-ESO-1 mAbs and was used in the successive experiments. Sections were subsequently incubated with anti-GAGE mAb M3 [1/100; produced in-house (Gjerstorff et al, 2006)], anti-GAGE-7 mAb (1/2000; Clone 26, BD Biosciences), anti-MAGE-A1 mAb (1/200; Clone MA454, Lab Vision Corporation, Newmarket Suffolk, UK), anti-NY-ESO-1 mAb (1/25; Clone E978, Zymed Laboratories Inc., San Francisco, CA, USA), anti-p450scc pAb (1/8.000; Corgen Inc., Taipei, Taiwan), anti-SF-1 pAb (1/500; a gift from Professor Ken-Ichirou Morohashi, National Institute of Natural Sciences, Aichi, Japan) or anti-OCT3/4 mAb (1/400; Clone C10, Santa Cruz Biotechnology, Heidelberg, Germany) diluted in antibody diluent (S2022, DAKO, Glostrup, Denmark) for 1 h at room temperature. Sections were washed with TNT buffer and incubated with horseradish peroxidase (HRP)-conjugated 'Ready-to-use' EnVision TM þ polymer K4001 (mouse mAb) or polymer K4003 (rabbit pAb) (DAKO) for 30 min, followed by another wash with TNT buffer.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development

Gjerstorff

Kock²,

Nielsen³

et al. 2007

Human Reproduction

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BACKGROUND: Cancer/testis antigens (CTAs) are expressed in several cancers and during normal adult male germ cell differentiation. Little is known about their role in fetal development of human germ cells. METHODS: We examined expression of the CTAs MAGE-A1, GAGE and NY-ESO-1 in fetal gonads by single and double immunohistochemical staining. RESULTS: We found that GAGE was expressed in the primordial germ cells of the gonadal primordium, whereas MAGE-A1 and NY-ESO-1 were first detected in germ cells of both testis and ovary after sexual differentiation was initiated. The number of positive germ cells and the staining intensity of all three CTAs peaked during the second trimester and gradually decreased towards birth in both male and female germ cells. In oocytes, MAGE-A1 expression terminated around birth, whereas NY-ESO-1 expression persisted through the neonatal stage and GAGE expression was maintained until adulthood. The population of GAGE-expressing male and female germ cells partially overlapped the population of OCT4-positive cells, whereas MAGE-A1 and NY-ESO-1 were clearly expressed only by OCT4-negative cells. CONCLUSIONS: Our results suggest that MAGE-A1 and NY-ESO-1 are associated with highly proliferating germ cells, whereas GAGE proteins have a more general function in germ cells unrelated to any specific developmental stage. The recognition of differential cellular expression of GAGE, MAGE-A1, NY-ESO-1 and OCT4 may help define biologically distinct germ cell subpopulations.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

See 1 more Smart Citation

MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development

Gjerstorff

Kock²,

Nielsen³

et al. 2007

Human Reproduction

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“…We previously observed similar staining intensity variability in breast cancer cell lines using an antibody reactive with another antigen (cancer/testis antigen GAGE; ref. 42). In those studies, only 5% to 30% of the experimental cancer cell line stained for GAGE, showing that expression of this antigen was not associated with a specific genotype but was linked to a specific phenotype (e.g., a specific stage in the cell cycle).…”

Section: Discussionmentioning

confidence: 99%

Phage Display–Derived Human Monoclonal Antibodies Isolated by Binding to the Surface of Live Primary Breast Cancer Cells Recognize GRP78

Jakobsen

Rasmussen

Laenkholm³

et al. 2007

Cancer Research

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Clinical trials using monoclonal antibodies (mAb) against cell-surface markers have yielded encouraging therapeutic results in several cancer types. Generally, however, anticancer antibodies are only efficient against a subpopulation of cancers, and there is a strong need for identification of novel targets and human antibodies against them. We have isolated single-chain human mAbs from a large naïve antibody phage display library by panning on a single-cell suspension of freshly isolated live cancer cells from a human breast cancer specimen, and these antibodies were shown to specifically recognize cancer-associated cell-surface proteins. One of the isolated human antibody fragments, Ab39, recognizes a cellsurface antigen expressed on a subpopulation of cancer cell lines of different origins. Immunohistochemical analysis of a large panel of cancerous and normal tissues showed that Ab39 bound strongly to several cancers, including 45% breast carcinomas, 35% lung cancers, and 86% melanomas, but showed no or weak binding to normal tissues. A yeast twohybrid screen of a large human testis cDNA library identified the glucose-regulated protein of 78 kDa (GRP78) as the antigen recognized by Ab39. The interaction was confirmed by colocalization studies and antibody competition experiments that also mapped the epitope recognized by Ab39 to the COOH terminus of GRP78. The expression of GRP78 on the surface of cancer cells, but not normal cells, makes it an attractive target for cancer therapies including mAb-based immunotherapy. Our results suggest that the human antibody Ab39 may be a useful starting point for further genetic optimization that could render it a useful diagnostic and therapeutic reagent for a variety of cancers. [Cancer Res 2007;67(19):9507-17]

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“…GAGE proteins have been shown to be expressed in a subset of oocytes of resting primordial follicles and in maturing oocytes (35) which limits their potential application as cancer biomarkers as well as antigen specific immunotherapy.…”

Section: Gage (G Melanoma Antigen) Familymentioning

confidence: 99%

Cancer-Testis Antigens: A Novel Group of Tumor Biomarkers in Ovarian Cancers

et al. 2016

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Context: Ovarian cancer is the most fatal gynecological malignancy with no effective screening strategy for early detection. As most cases are being detected in advance stages, conventional therapies are not beneficial for the majority of patients. Cancer-testis antigens (CTAs) are a group of tumor associated antigens with specific expression pattern in cancers which potentiate them for application as cancer biomarkers and targets for immunotherapy. Evidence Acquisition: We performed a computerized search of the MEDLINE/PUBMED databases with key words: ovarian cancer, cancer-testis antigen, biomarker and immunotherapy.

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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

Cited by 53 publications

References 37 publications

MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development

MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development

Phage Display–Derived Human Monoclonal Antibodies Isolated by Binding to the Surface of Live Primary Breast Cancer Cells Recognize GRP78

Cancer-Testis Antigens: A Novel Group of Tumor Biomarkers in Ovarian Cancers

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