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MGEA6 Is Tumor-Specific Overexpressed and Frequently

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Oncogene (2002) 21, 239 ± 247 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc MGEA6 is tumor-speci®c overexpressed and frequently recognized by patient-serum antibodies Nicole Comtesse1, Isolde Niedermayer2, Brenda Glass1, Dirk Heckel1, Esther Maldener1, Wolfgang Nastainczyk3, Wolfgang Feiden2 and Eckart Meese*,1 1Institut fuÈr Humangenetik, UniversitaÈtskliniken des Saarlandes, 66421 Homburg/Saar, Germany; 2Abteilung fuÈr Neuropathologie, UniversitaÈtskliniken des Saarlandes, 66421 Homburg/Saar, Germany; 3Institut fuÈr Medizinische Biochemie, UniversitaÈtskliniken des Saarlandes, 66421 Homburg/Saar, Germany Tumorigenesis of meningioma has been associated with 40% of the meningiomas show no mutation in the NF2 chromosome 22, most notably the NF2 gene, but gene, indicating that other genes are involved in the additional genes have also been implicated in meningioma tumorigenesis (Ruttledge et al., 1994; Akagi et al., development. Previously, we have cloned the cDNAs for 1995). the meningioma expressed antigen 6 (MGEA6) and its A variety of tumors are known to elicit immune splice variant MGEA11. Here, we show that antibodies responses in patients bearing the tumor. Immunogenic against recombinantly expressed MGEA6/11 are found in tumor-associated antigens have been described pri- 41.7% (10/24) of the sera from meningioma patients and marily for malignant tumors including melanoma, in 2/8 sera of glioblastoma patients, whereas no response breast cancer, colon cancer, ovarian cancer (Real et was seen in 12 sera from healthy persons. Western-blot al., 1988; Ben-Mahrez et al., 1990; Gallagher et al., analyses using generated polyclonal antibodies, revealed 1991; Disis et al., 1994; Disis and Cheever, 1996; overexpression in meningioma and glioma tumor samples Boon and Lloyd, 1997). However, dierent studies compared to normal brain. Immunohistochemical staining have indicated that meningiomas are also capable of of tissue sections con®rms reactivity in meningioma tumor inducing an immune response in the host. In 1976, cells and tumor cells of glial origin. We found no Pees and Seidel already described a cellular immune reactivity to normal astrocytes and only faint reactivity response against autologous and heterologous menin- to normal leptomeninges. Sequence analysis predicted gioma cells in the serum of patients (Pees and Seidel, membranic localization of MGEA6/11, that was con- 1976). Another study concerning a cytotoxic immune ®rmed by cell fractionation. The immune response to response presents data suggesting that meningiomas MGEA6/11 is frequent in both meningioma and glioma can induce complex immunological responses in the patients and may likely be attributed to overexpression of host (Pees, 1979). The presence of IgG in meningioma the MGEA6/11 protein in the tumor cells. was shown by Tabuchi et al. (1979). Expression of Oncogene (2002) 21, 239 ± 247. DOI: 10.1038/sj/onc/ MHC class II and MHC class I molecules have also 1205005 been detected in meningioma tissue (Becker and Roggendorf, 1989). Keywords: tumor antigen; overexpression; central- Previously, we reported cloning of immunoreactive nervous-system neoplasm; meningioma; glioma antigens expressed in meningioma, providing the ®rst evidence for the expression of immunogenic antigens in this tumor type (Heckel et al., 1997, 1998; Comtesse et Introduction al., 1999). The meningioma expressed antigens 6/11 (MGEA6/11; previously called MEA6/11) induced an Meningiomas are neoplasms of the leptomeninges immune response in the patient bearing the meningioma covering the brain and the spinal cord. With *20% (Heckel et al., 1997). Expression analysis on the mRNA of all primary intracranial tumors, they are among the level revealed constitutive expression of the MGEA6/11 most common tumors of the human nervous system in all human tissues tested. MGEA6 belongs to a (Kleihues and Cavenee, 2000). Although there is a multigene family with an active locus on chromosome large amount of evidence for involvement of the 14q and at least nine pseudogenes on dierent neuro®bromatosis type 2 (NF2) gene in tumor growth, chromosomes. The smaller MGEA11 is generated by alternative splicing of exon 19 of the MGEA6 gene (Comtesse et al., 2001). In this study we report that the immune response *Correspondence: E Meese, Department of Human Genetics, against MGEA6/11 is found in 41.7% (10/24) of University of Saarland, Building 60, 66421 Homburg/Saar, meningioma and in 2/8 of glioblastoma patients, with Germany; E-mail: [email protected] Received 19 June 2001; revised 28 September 2001; accepted 1 no antibodies present in 12 sera of healthy persons, October 2001 indicating that MGEA6/11 probably acts as a tumor MGEA6 is overexpressed and immunogenic N Comtesse et al 240 antigen in these tumor types. We report that on the protein level, MGEA6/11 is overexpressed in menin- gioma and glioma tumor cells compared to the normal tissue. Immunohistochemical staining of tissue sections revealed reactivity of meningioma cells and tumor cells of glial origin, whereas no reactivity was found in the cellular elements of the normal control brain and only faint reactivity in normal leptomeninges. No expression was found in tumor cells of cerebral carcinoma metastases. Sequence analysis purported a membranic localization of the protein, which was con®rmed by Western-blot analysis of cellular fractions of MGEA6/ 11 expressing cells. Our ®ndings suggest that the immune response in glioma and meningioma patients may likely be attributed to overexpression of this gene at the protein level. Results Recombinant expression of MGEA6/11 in a eukaryotic expression system To further characterize the meningioma expressed antigens 6 and 11 (MGEA6/11), we expressed the two variants in a recombinant eukaryotic expression system. As shown previously, cDNA for MGEA6 shows an open reading frame (ORF) of 2415 bp and cDNA for MGEA11 an ORF of 2286 bp, with the coding regions diering only in a 129 bp sequence (Heckel et al., 1997). As most recently described, Figure 1 Western-blot analyses using recombinantly expressed mRNA for MGEA11 probably results from alternative MGEA6/11. (a) Serum of meningioma patient H4 detects a 110 kDa and a 105 kDa protein corresponding to MGEA6 and splicing of exon 19 of the MGEA6 gene on chromo- MGEA11. (b) Detection of MGEA6 and MGEA11 with serum some 14q (Comtesse et al., 2001). Sequence analysis of from glioblastoma patient H57. (c, left) Western blot with three the cDNA clones revealed a high number of codons pooled normal sera. Reactivity of the sera was shown using a rarely used in bacteria. Therefore, we used the positive control (data not shown). (Right) Same blot as left, stripped and incubated with meningioma serum H4 detecting baculovirus expression system to facilitate complete MGEA6 and 11. NR: not recombinant clone translation of the clones. After recombinant expression, the proteins were visualized by Western blot analysis using the serum of the autologous patient for detection. We determined molecular masses for MGEA6 of subtype of meningiomas (Tables 1 and 2). In detail, we 110 kDa and for MGEA11 of 105 kDa (Figure 1a). found antibodies against MGEA6/11 in 4/10 sera from Deducting the fusion portion of 34AA (about 4 kDa), WHO grade I meningiomas including arachnothelial, results in a molecular mass of 106 kDa for MGEA6 transitional and secretory subtypes, in 5/12 sera from and of 101 kDa for MGEA11. This is in good atypical meningiomas, and in one of two sera from accordance with the predicted theoretical molecular anaplastic meningioma. masses of 91 kDa for MGEA6 and 89 kDa for We further tested sera from patients with primary MGEA11. The minimal mass dierences can be brain tumors of glial origin (Table 2). We detected attributed to post-translational modi®cation. antibodies against MGEA6 in 2/8 sera from glioblas- toma (WHO grade IV) patients (Figure 1b) and in one of two patients with WHO grade II astrocytomas. Humural immune response against MGEA6/11 is found in Sera derived from two patients with WHO grade III meningioma and glioma patients, not in healthy persons astrocytomas and from three patients with pilocytic We also used the baculovirus-expressed recombinant astrocytomas did not react with MGEA6/11. When proteins to examine the immune response against using 12 sera from healthy, tumor-free persons, in no MGEA6/11 in other patients bearing meningiomas. case was an antibody response detected against We tested 24 sera derived from patients with MGEA6/11 (Figure 1c). Additionally, for testing meningioma of dierent grading and histological tumors derived from other embryonic origin, we tested subtype. An antibody reaction was detected with 10 six sera of patients with squamous cell lung of 24 (41.7%) meningioma sera. The immune response carcinoma. In no case were antibodies against was not correlated with tumor grading or histological MGEA6/11 found. Oncogene MGEA6 is overexpressed and immunogenic N Comtesse et al 241 Table 1 Summary of sera from meningioma-patients examined for C-terminal region is characterized by a high percentage antibody-response against MGEA6 (22%) of proline residues including several polyproline Meningioma Immune stretches. Notably, the insertion found in MGEA6 also No WHO grading Subtype response possesses a high amount of proline residues and shows H 4 WHO I Arachnothelial + high hydrophobicity. H 19 WHO I Transitional + H 28 WHO I Arachnothelial 7 H 52 WHO I Secretory 7 Generation of polyclonal antibodies against MGEA6/11 H 53 WHO I Arachnothelial 7 via peptide immunization H 63 WHO I Transitional, regressive + H 64 WHO I Angiomatous, regressive 7 To investigate the MGEA6/11 expression at the protein H 71 WHO I Secretory 7 level, we generated polyclonal rabbit antibodies against H 78 WHO I Fibroblastic 7 MGEA6/11. We synthesized a peptide from the C- H 81 WHO I Secretory + terminus of MGEA6/11. For immunization, the H 15 WHO II Atypical 7 peptide was coupled with an additional N-terminal H 60 WHO II Atypical + cysteine residue to keyhole limpet hemocyanine.
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