Identification of C-Met Oncogene as a Broadly Expressed Tumor-Associated Antigen Recognized by Cytotoxic T-Lymphocytes

Schag, Kerstin; Schmidt, Susanne; Müller, Martin; Weinschenk, Toni; Appel, Silke; Weck, Markus M.; Grünebach, Frank; Stevanović, Stefan; Rammensee, Hans‐Georg; Brossart, Peter

doi:10.1158/1078-0432.ccr-03-0640

Cited by 36 publications

(28 citation statements)

References 37 publications

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“…In addition to CA-IX, ADFP, Cyclin D1, C-MET, and RGS-5 are also overexpressed in ccRCC (14). In contrast to published reports (33,34), we found that ADFP expressed more frequently (65%) than C-MET (30%). Cyclin D1 is a cell-cycle regulator crucial for the G 1 -S transition (35) and is overexpressed in many cancers including colorectal and breast carcinoma (36,37).…”

Section: Discussioncontrasting

confidence: 96%

“…ADFP, C-MET, and RSG-5 are not immunogenic in patients with ccRCC, as we did not detect T-cell responses specific for these antigens, despite their frequent overexpression. This finding is in agreement with previously published data on rare T-cell responses in patients with ccRCC (15), even though ADFP-and C-MET-specific T cells could be expanded from the blood of healthy donors (33,34). RGS-5 overexpression did not result in detectable RGS-5-specific T-cell responses in our cohort, although such responses were reported in the blood of healthy donors and patients with acute myeloid leukemia (42).…”

Section: Discussionsupporting

confidence: 93%

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Spontaneous Peripheral T-cell Responses toward the Tumor-Associated Antigen Cyclin D1 in Patients with Clear Cell Renal Cell Carcinoma

Dannenmann

Hermanns

Bransi

et al. 2013

Cancer Immunology Research

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Renal cell carcinoma (RCC) is a heterogeneous group of kidney cancers with clear cell RCC (ccRCC) as the major subgroup. To expand the number of clinically relevant tumor-associated antigens (TAA) that can be targeted by immunotherapy, we analyzed samples from 23 patients with primary ccRCC for the expression and immunogenicity of various TAAs. We found high-frequency expression of MAGE-A9 and NY-ESO-1 in 36% and 55% of samples, respectively, and overexpression of PRAME, RAGE-1, CA-IX, Cyclin D1, ADFP, C-MET, and RGS-5 in many of the tumor samples. We analyzed the blood of patients with HLA-A2 þ ccRCC for the presence of CD8 þ T cells specific for TAA-derived HLA-A2-restricted peptides and found spontaneous responses to cyclin D1 in 5 of 6 patients with Cyclin D1-positive tumors. Cyclin D1-specific CD8 þ T cells secreted TNF-a, IFN-g, and interleukin-2 (IL-2), and degranulated, indicating the presence of polyfunctional tumor-specific CD8 þ T cells in the blood of these patients with ccRCC. The high frequency (43%) of Cyclin D1 overexpression and the presence of functional cyclin D1-specific T cells in 83% of these patients with ccRCC suggest that cyclin D1 may be a target for immunotherapeutic strategies. Cancer Immunol Res; 1(5); 288-95. Ó2013 AACR.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 93%

Spontaneous Peripheral T-cell Responses toward the Tumor-Associated Antigen Cyclin D1 in Patients with Clear Cell Renal Cell Carcinoma

Dannenmann

Hermanns

Bransi

et al. 2013

Cancer Immunology Research

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“…PCR products were sequenced to confirm correct amplification. Control primers for glyceraldehyde-3-phosphate dehydrogenase are TCA AGG TCG AGT CAA CGG ATT TGG T and CAT GTG GGC ATG AGG TCC ACC AC, amplifying 983 bp, as described (Clontech), and control primers for ␤2-microglobulin are GGG TTT CAT CCA TCC GAC AT and GAT GCT GCT TAC ATG TCT CGA, amplifying 224 bp, as described (32).…”

Section: Methodsmentioning

confidence: 99%

PAX6 Is Expressed in Pancreatic Cancer and Actively Participates in Cancer Progression through Activation of the MET Tyrosine Kinase Receptor Gene

Mascarenhas

Young

Littlejohn

et al. 2009

Journal of Biological Chemistry

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Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.Pancreatic cancer is an aggressive and deadly disease, with an average median survival of less than a year (1). Several genetic pathways have been identified as being active in the progression of this tumor, including signaling through MET (MET tyrosine kinase receptor protein). The MET gene encodes a tyrosine kinase receptor for the ligand hepatocyte growth factor/scatter factor. The MET gene produces a partially glycosylated 170-kDa precursor protein. This precursor is glycosylated further and cleaved into a 50-kDa ␣ chain and a 140-kDa ␤ chain to create a mature receptor (2). The MET receptor is essential for normal development and plays a role in cell migration, growth, survival, differentiation, angiogenesis, and tube formation/ branching morphogenesis (reviewed in Ref.3). MET has also been implicated in cancer progression and is directly involved in metastasis, resistance to apoptosis, and tumor growth.MET is expressed in the developing pancreatic bud of the embryo and marks candidate stem/progenitor cells in the embryonic and adult pancreas (4 -6). MET expression is expressed at very low levels in normal adult differentiated pancreatic cells (7). MET is overexpressed in pancreatic cancer cells and has been linked to the aggressiveness of this tumor in terms of growth, invasion, and metastasis (7-10).Although mutations in the MET locus have been identified, overexpression of MET occurs mainly due to aberrant transcriptional regulation (3). The MET gene is regulated by several transcription factors that can either activate or repress expression. Activators include HIF1 (hypoxia-induced factor 1) in response to oxygen deficiency (11), ETS1 (12), Sp1 (13), AP1 (14), Smads downstream of transforming growth factor-␤ signaling (13), and the p53 protein (15) The transcription factor PAX3 can also activate MET expression during the embryonic development of muscle cells (23). PAX3 belongs to the PAX gene family, and most of what is known about these related proteins is their role during development. Only recently has the expression of PAX proteins in adult stem cells and in disease been discovered...

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“…A volume of 1.0 ml of cDNA was subjected to PCR (32 cycles) as described earlier. 21,22 The integrity of the RNA and the efficiency of the cDNA synthesis were checked by amplifying the b2-microglobulin gene with an intron-spanning primer pair. Primer sequences were deduced from published cDNA sequences: ERK2 5 0 -ccacc catatctggagcagt-3 0 and 5 0 -cagtcctctgagcccttgtc-3 0 , IRAK1 5 0 -gacc ctgtctctgccaaaaa-3 0 and 5 0 -caggctggagtgcagtcata-3 0 and MyD88 5 0 -gcacatgggcacatacagac-3 0 and 5 0 -gacatggttaggctccctca-3 0 .…”

Section: Reverse Transcription-pcrmentioning

confidence: 99%

“…Remaining sequences were published elsewhere. 21,22 The semiquantitative estimation of target gene expression was carried out by normalization of the density volumes of ethidium bromidestained PCR products to the corresponding b2-microglobulin-PCR products (target gene-PCR product [S {pixel, gray values}]/ b2-microglobulin [S {pixel, gray values}]) using a CCD camera and gel analysis system (BioDocAnalyze video, Whatman Biometra, Gö ttingen, Germany). 23 Values were expressed as percentage of the 24 h value with IL-4 and GM-CSF (100%).…”

Section: Reverse Transcription-pcrmentioning

confidence: 99%

Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

et al. 2008

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Identification of C-Met Oncogene as a Broadly Expressed Tumor-Associated Antigen Recognized by Cytotoxic T-Lymphocytes

Abstract: Conclusion: Our results demonstrate that c-Met oncogene is a novel tumor rejection antigen recognized by CTL and expressed on a broad variety of epithelial and hematopoietic malignant cells.

Cited by 36 publications

References 37 publications

Spontaneous Peripheral T-cell Responses toward the Tumor-Associated Antigen Cyclin D1 in Patients with Clear Cell Renal Cell Carcinoma

Spontaneous Peripheral T-cell Responses toward the Tumor-Associated Antigen Cyclin D1 in Patients with Clear Cell Renal Cell Carcinoma

PAX6 Is Expressed in Pancreatic Cancer and Actively Participates in Cancer Progression through Activation of the MET Tyrosine Kinase Receptor Gene

Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

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