Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens

Abstract

Little is known about the function of human cancer͞testis antigens (CTAs), such as MAGE, BAGE, GAGE, HOM-MEL-40, and NY-ESO-1, the expression of which is restricted to human malignancies and testis. When screening a cDNA expression library enriched for testis-specific representative long transcripts for reactivity with high-titered IgG antibodies from the serum of a patient with renal cell carcinoma, one repeatedly detected antigen, designated HOM-TES-14, turned out to be encoded by the synaptonemal complex protein 1 (SCP-1) gene. SCP-1 is known to be selectively expressed during the meiotic prophase of spermatocytes and is involved in the pairing of homologous chromosomes, an essential step for the generation of haploid cells in meiosis I. Investigation of a broad spectrum of normal and malignant tissues revealed expression of SCP-1 transcripts and antigen selectively in a variety of neoplastic tissues and tumor cell lines. Immunof luorescence microscopy analysis with specific antiserum showed a cell cycle phaseindependent nuclear expression of SCP-1 protein in cancer cells. SCP-1 differs from other members of the class of CTA by its localization on chromosome 1 and its frequent expression in malignant gliomas, breast, renal cell, and ovarian cancer. The aberrant expression of SCP-1 in tumors might contribute to their genomic instability and suggests that the functional role of other CTA might also relate to meiosis.The identification of genes that are selectively expressed in cancer and code for proteins inducing a specific immune response in the tumor-bearing host is the prerequisite for specific immunotherapeutic approaches to cancer. By using cytotoxic T lymphocyte-and antibody-based approaches, several human tumor antigens have been defined that might be suitable targets for specific cancer vaccination (1, 2). The difficulties in establishing cytotoxic T lymphocyte clones with specificity to human neoplasms are the major reason whywith the exception of RAGE (renal cell cancer-associated antigen) (3)-all T cell-defined human tumor antigens have been originally described in malignant melanoma. Immunotherapeutic approaches to human neoplasms other than melanoma are restricted to the nonmelanoma cases that express the melanoma-defined antigens. To overcome this limitation, we recently established SEREX (serological analysis of antigens by recombinant expression cloning) that allows for the unbiased search of tumor antigens that elicit IgG antibody responses in the autologous tumor patients (4). With this approach, we have identified multiple tumor antigens in different human neoplasms. Among others, we detected MAGE-1 (melanoma-associated antigen) and MAGE4a transcripts, demonstrating that at least some of the serologically identified antigens are also targets for cytotoxic T cells.

Expression of multiple cancer-testis antigen genes in gastrointestinal and breast carcinomas

“…These results suggest that if SCP-1 is a new target antigen in addition to MAGE-1 and MAGE-3, the candidates for CTA-based cancer immunotherapy for gastric and breast carcinomas will be increased in number. SCP-1 was identified as HOM-TES-14, during screening of a cDNA library enriched for testis-specific clones with serum from a renal cell carcinoma patient (Türeci et al, 1998b). High levels of expression of SCP-1 in tumour tissue and normal testis are recognized at the mRNA and protein levels by RT-PCR and Western blot analysis, respectively.…”

“…The presence of MAGE-1 and MAGE-3 cDNA in the reverse transcription products was detected by polymerase chain reaction (PCR) amplification in separate reactions, using oligonucleotide primers located in the different exons of each gene (Weynants et al, 1994). The presence of NY- and SCP-1 were determined by PCR amplification under the same conditions as reported previously (Lethe et al, 1998, Türeci et al, 1998a, Türeci et al, 1998b. Briefly a 1/100 aliquot of reverse transcription products were amplified in a 30 µl reaction mixture containing 10 nmoles of each dNTP (dATP, dTTP, dCTP, dGTP.…”

“…The method has enabled the discovery of several novel genes with tumour specificity, such as NY-ESO-1 , LAGE. (Lethe et al, 1998), SCP-1 (Türeci et al, 1998b), SSX (Türeci et al, 1996) and CT7 (Chen et al, 1998). These antigens are also expected to become new candidates for cancer-specific immunotherapy, but little information is available on the comprehensive expression of CTAs in a large number of samples of gastrointestinal and breast carcinomas.…”

Sperm-associated antigen 1 is expressed early in pancreatic tumorigenesis and promotes motility of cancer cells

“…Pancreatic CT genes are among the least studied; the latest report of Kubuschok et al (2004) shows that out of 10 different CT genes analysed, only HOM-TES-14/ SCP-1 and GAGE were expressed in a significant proportion of pancreatic tumour cases (48 and 21%, respectively), SCP-1 (synaptonemal complex protein) is expressed in almost 50% of PDAC specimens (Tureci et al, 1998), whereas D40/CT29 was found expressed in not more than 27% of PDACs (Takimoto et al, 2002). Except for SCP-1, which plays an important role in the alignment of the two homologous chromosomes, in promoting crossing-over events and ensuring chromosome segregation in meiosis (Tureci et al, 1998), the function of the remaining CT genes is completely unknown.…”

“…Except for SCP-1, which plays an important role in the alignment of the two homologous chromosomes, in promoting crossing-over events and ensuring chromosome segregation in meiosis (Tureci et al, 1998), the function of the remaining CT genes is completely unknown.…”