Characterization of monoclonal antibodies to human melanoma-associated antigens

The hybridomas No. 165.28T, No. 473.54S, and No. 653.25N derived from the fusion of myeloma cells with splenocytes from mice immunized with cultured human melanoma cells secreted monoclonal antibodies recognizing antigenic determinants maximally expressed on cultured human melanoma cells and freshly explanted melanoma cells. Monoclonal antibody No. 376.74T reacted also with carcinoma cell lines but with a significantly lower titer. Rosette inhibition assay showed that these antigenic determinants were expressed on antigenic structures, which are not associated with beta 2 microglobulin and histocompatibility antigens. Two monoclonal antibodies recognized the same or closely associated antigenic determinants, and the remaining two monoclonal antibodies reacted with distinct antigenic determinants. All four monoclonal antibodies could mediate antibody-dependent cellular cytotoxicity of cultured melanoma cells, but none could mediate complement-dependent cytotoxicity.     

Expression of melanoma-associated antigens by normal and neurofibroma Schwann cells

The cell surface antigen distribution on traumatic neuroma Schwann cells and neurofibroma Schwann-like cells was characterized using monoclonal antibodies that define melanoma-associated antigens. Immunofluorescence staining of cultured cells, immunoprecipitation of radioiodinated antigens from cells placed in short-term cultures, and immunoperoxidase staining of frozen tissue sections revealed most of the melanoma-associated antigens tested on traumatic neuroma and neurofibroma Schwann cells and on fetal and adult femoral nerve. The cross-reactivity of the antibodies with neural cells may reflect the common neural crest embryological origin of Schwann cells and melanocytes. Cell sorter analysis of neurofibroma cells using a monoclonal antibody directed against the melanoma nerve growth factor receptor resulted in cell cultures highly enriched for Schwann-like cells which may bear the genetic defect responsible for neurofibromatosis. The antigen detected by this monoclonal antibody is the neurofibroma nerve growth factor receptor and the antibody was a potent inhibitor of nerve growth factor binding to neurofibroma cells.     

Clinical application of monoclonal antibodies to human malignant melanoma-associated antigens

Monoclonal antibodies to human malignant melanoma-associated antigens were reviewed from the viewpoint of the target structure recognized by them. With regard to clinical application of monoclonal antibodies for diagnosis, immunohistochemistry, serological diagnosis and tumor imaging were described, together with the possibility of therapy involving monoclonal antibody infusion.     

Cancer-retina antigens as potential paraneoplastic antigens in melanoma-associated retinopathy

Melanoma-associated retinopathy is a rare paraneoplastic neurological syndrome characterized by retinopathy in melanoma patients. The main photoreceptor proteins have been found to be expressed as cancer-retina antigens in melanoma. Here we present evidence that these can function as paraneoplastic antigens in melanoma-associated retinopathy. Sera and one tumor cell line of such patients were studied and ret-transgenic mice spontaneously developing melanoma were used as a murine model for melanoma-associated retinopathy. Splenocytes and sera were used for adoptive transfer from tumor-bearing or control mice to wild-type mice. Retinopathy was investigated in mice by funduscopy, electroretinography and eye histology. Expression of photoreceptor proteins and autoantibodies against arrestin and transducin were detected in melanoma-associated retinopathy patients. In tumor-bearing ret-transgenic mice, retinopathy was frequently (13/15) detected by electroretinogram and eye histology. These pathological changes were manifested in degenerations of photoreceptors, bipolar cells and pigment epithelium as well as retinal detachment. Mostly these defects were combined. Cancer-retina antigens were expressed in tumors of these mice, and autoantibodies against arrestin were revealed in some of their sera. Adoptive transfer of splenocytes and sera from tumor-bearing into wild-type mice led to the induction of retinopathy in 4/16 animals. We suggest that melanoma-associated retinopathy can be mediated by humoral and/or cellular immune responses against a number of cancer-retina antigens which may function as paraneoplastic antigens in melanoma-associated retinopathy.     

Mouse monoclonal antibody (FKH1) detecting human melanoma-associated antigens

A mouse monoclonal antibody, FKH1, was produced to detect cytoplasmic melanoma-associated antigen. FKH1 was raised using cultured human melanoma cell line KHm-6 as an immunogen. Reactivity of this antibody was assessed by immunohistochemical techniques against cell lines and normal and neoplastic tissues. Positive reactions were seen against 5 human melanoma cell lines. It stained cytoplasm of melanoma cells in a diffuse and granular pattern in indirect immunofluorescence. Immunoelectron microscopy showed diffuse distribution of immunoreactant in the cytoplasm of KHm-1 cells excluding melanosomes and other organelles. Reactivity against frozen and alcohol-fixed, paraffin-embedded melanocytic tumors was also tested with IIF or indirect or avidin biotinylated horseradish peroxidase complex immunoperoxidase techniques. All cases of frozen sections from benign and malignant melanocytic tumors showed positive staining with FKH1. In fixed tissues, however, reactivity was 11 of 14 (79%) in malignant melanoma and 28 of 42 (67%) in other melanocytic tumors. FKH1 did not react against normal melanocytes and nonmelanocytic tumors except APUDoma and 2 glioblastoma cell lines. It failed to stain the B-16 mouse melanoma cell line, neuroblastoma cell line, breast carcinoma cell line, and T-cell lymphoma cell line. Normal human peripheral nerves were nonreactive with FKH1. In immunoelectroblot study, FKH1 bound with proteins having molecular weight of 71,000 and 55,000 extracted from KHm-6 cells. It was suggested that FKH1 is a useful monoclonal antibody in diagnostic study of human malignant melanoma specimens.     

Step-wise expression of melanoma-associated antigens in tumor progression

Selection of monoclonal antibodies for differential reactivity with benign and malignant melanocytic lesions has led to the identification of molecules which may be involved in the development of metastases. Based on the observed alterations in the antigenic profile we propose a scheme representing the tumor progression of melanocytes to metastatic melanoma.     

Endocrine responsiveness in human melanocytes and melanoma cells in culture

Studies were performed for the investigation of endocrine responsiveness in cell lines derived from either normal human melanocytes or human melanoma cells. Alterations in differentiation (tyrosinase activity) were determined in cells exposed to either melanocyte-stimulating hormone (MSH, 10(-7) M), theophylline (10(-3) M), N6,O2'-dibutyryl cyclic AMP (db-cAMP, 10(-4) M), or prostaglandin E1 (PGE1, 10(-6) M). Cultures derived from normal uveal melanocytes demonstrated increased tyrosinase activity upon exposure to either theophylline, db-cAMP, or PGE1, but not to MSH. However, MSH responsiveness was detected in 7 of 11 human melanoma cell lines. Four cell lines demonstrated increased activity of tyrosinase after MSH treatment, whereas three lines showed an MSH-induced inhibition of enzyme activity. PGE1 was effective in stimulating tyrosinase activity in five of nine cell lines examined. Theophylline was the most effective stimulator of tyrosinase in melanoma-derived cell populations and caused increased enzyme activity in eight of eleven cell lines.     

Characterization of melanoma-associated surface antigens involved in the adhesion and motility of human melanoma cells

The functional properties of the melanoma-associated antigens detected by monoclonal antibodies (MAbs) AMF-6 and AMF-7 were investigated. These MAbs were selected previously because of their capacity to block the anti-melanoma reactivity of cytotoxic T-lymphocyte clones AMF-6 and AMF-7 detect a melanoma-associated proteoglycan (MW greater than 450-250 kDa) and a molecular complex, which under reducing conditions consists of 4 compounds of 120, 95, 29 and 25 kDa respectively. AMF-6 reacted strongly with all 30 cultured melanomas and all 41 melanomas in frozen tissue sections. Significant cross-reactivity was only observed with nevi and perineurium, whereas normal skin melanocytes were negative. AMF-7 reacted with all 25 cultured melanomas and all 34 melanomas in frozen sections. AMF-7 cross-reacted with a proportion of nevi and endothelial cells from small vessels. The antigen detected by AMF-6 and AMF-7 could not be modulated by retinoic acid or recombinant gamma-IFN, which induced or enhanced the expression of HLA-DR, HLA-DQ and Class-I MHC antigens. In addition, the antigens were not readily modulated when cells were incubated in excess amounts of AMF-6 and AMF-7. Interestingly, the antigen detected by AMF-7 was strongly associated with the adhesion and cytoplasmic spreading of melanoma cells to plastic surfaces and monolayers of vascular endothelial cells. AMF-6 did not block the adhesion of melanoma cells but delayed cytoplasmic spreading. Both AMF-6 and AMF-7 blocked fibronectin-induced chemotaxic motility and chemokinesis of melanoma cells. In addition to their membrane localization, the antigens detected by AMF-6 and AMF-7 were also abundant in extracellular adhesion plaques deposited by cultured melanoma cells. Our results indicate that the high-MW melanoma-associated proteoglycan and the antigen detected by AMF-7 are associated with adhesion and/or cytoplasmic spreading and motility of human melanoma cells, suggesting that these antigens are associated with the (hematogenic) dissemination of human melanoma. This is supported by the finding that AMF-7 stained primary tumors heterogeneously, whereas metastases were homogeneously stained.     

Flow cytometric determination of the frequency and heterogeneity of expression of human melanoma-associated antigens

We used flow cytometry to measure the expression of human melanoma antigens on cell suspensions dissociated from metastatic masses. The objective was to study the heterogeneity between tumor samples from different patients and between different tumors excised from a single patient. Fifty-three metastases excised from 34 melanoma patients were analyzed with a panel of nine murine monoclonal antibodies (MOABs). Melanoma cells were stained by an indirect fluorescent method and analyzed on a Coulter EPICS C flow cytometer after gating to exclude tumor-infiltrating leukocytes and dead cells. The most consistently and most strongly expressed antigen was the high-molecular-weight proteoglycan (detected by the MOAB 9.2.27), which was expressed on 95% of the melanoma specimens and by a high proportion of cells within each specimen (mean +/- SE, 79.2 +/- 5.5). However, strong expression of this antigen was limited to melanoma cells that had been dissociated mechanically and was markedly diminished by exposure to collagenase. Culture of collagenase-dissociated tumor cells for 24 to 48 h resulted in reexpression of the antigen. The expression of other melanoma-associated antigens was not affected by collagenase treatment, but for these antigens there was more variability between cells from an individual tumor and between tumors from different patients. The percentage of enzyme-dissociated tumors considered positive for MOAB binding (defined as at least 10% of cells positive) and the mean +/- SE of the percentage of positive cells within a tumor were as follows: MOAB ME-9-61 (antigen, p97) = 84% + (41.2 +/- 5.4%); MOAB ME-20.4 (antigen, nerve growth factor receptor) = 40% + (18.7 +/- 5.1%); MOAB ME-24 (antigen, ganglioside GD3) = 84% + (50.8 +/- 4.8%); MOAB ME-311 (antigen, ganglioside 9-O-acetyl-GD3) = 76% + (42.5 +/- 5.1%); MOAB ME-361 (antigen, mainly ganglioside GD2) = 3% + (1.9 +/- 0.8%); MOAB 3F8 (antigen, ganglioside GD2) = 36% (10.5 +/- 3.8%); MOAB 14G2a (antigen, ganglioside GD2) = 86% + (46.0 +/- 6.7%); MOAB L243 (antigen, HLA-DR) = 56% + (22.5 +/- 5.5%). In 19 cases, we were able to compare the antigenic profiles of two tumors excised from the same patient at different times. Analysis by nonindependent t test showed no significant differences in MOAB binding between the paired tumors. Moreover, linear regression analysis indicated that there was a linear relationship, with a slope approximately = 1, between the percentage of positive cells in Tumor 1 versus Tumor 2.(ABSTRACT TRUNCATED AT 400 WORDS)     

Distribution and organelle specificity of melanoma-associated antigens identified by Mo 465.12 in human malignant melanoma

Mo 465.12 (Mo 465) is a unique monoclonal antibody that detects cytoplasmic antigens highly restricted to the cells of human malignant melanoma (MM). As yet, it is not known which cytoplasmic components are reactive with Mo 465 within MM cells. This study, using the enzyme-linked immunosorbent assay (ELISA) technique, examines the distribution and specificity of Mo 465-reactive proteins in MM tissues that were isolated by cell fractionation and solubilized by a nonionic detergent (Brij 35). Light microscopically, Mo 465 bound strongly to the cytoplasm of MM cells, being localized as patchy or microgranular, but not to the normal epidermal melanocytes. When the cultured MM cells were fractionated, Mo 465 reacted with both soluble and membrane fractions and with the spent culture medium. To further identify the organelle specificity of Mo 465-reactive proteins, metastatic human MM and normal human liver tissues were separated into the fractions of large granules, small granules, Golgi apparatus, mitochondria, rough endoplasmic reticulum (ER), smooth ER, microsomes, and melanosomes. Mo 465-reactive proteins were detected in the fractions of crude homogenate, microsomes, and rough ER of MM tissue, and their reactivities were in parallel to the concentration of solubilized protein. the findings indicate that Mo 465-reactive proteins are localized in rough ER, that they are released into the cytoplasm, and that in the in vitro condition they are shed into the culture medium.     

Identification and purification of 115- and 125-kilodalton cell surface human melanoma-associated antigens

Surface macromolecules shed into culture medium by radioiodinated human melanoma cells were fractionated on Sepharose 6B and by sequential lectin-affinity chromatography. Radioactivity associated with melanoma-associated antigens (MAAs) was assayed by indirect immunoprecipitation with anti-melanoma serum. Two MAAs were separated and highly purified. Both antigens were single-chain glycoproteins expressed on many, but not all, melanoma cells but undetectable on normal melanocytes and a variety of unrelated normal, fetal, and malignant cells. One MAA, with a molecular mass of approximately 115 kd, eluted on Sepharose 6B in a lower molecular mass peak and had a high affinity for ricin lectin. The carbohydrate side chain of this antigen contained D-galactose. The other MAA, with a molecular mass of approximately 125 kd, eluted on Sepharose 6B in a peak of higher molecular mass and had a high affinity for wheat germ lectin. The carbohydrate side chain of this antigen contained sialic acid. Both antigens were highly purified. By sodium dodecyl sulfate-poly-acrylamide gel electrophoresis analysis, no contaminating proteins were present in the purified 115-kd MAA fraction, and only a single minor contaminant was present in the fraction containing the purified 125-kd MAA. These two antigens differed in their biochemical or immunological properties from other MAAs of similar size that have been previously described.     

Mitofilin and titin as target antigens in melanoma-associated retinopathy

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic syndrome in patients with melanoma. Since the onset of MAR symptoms is often associated with tumor progression or recrudescence of metastases, MAR-related symptoms are prognostic relevant. The pathomechanism underlying MAR is supposed to result from antibody production against yet unknown melanoma-associated antigens that are also expressed in retinal tissue, leading to the destruction of retinal cells and resulting in defective signal transduction. Only a 35 kDa protein in Müller glial cells, a 22 kDa neuronal antigen and retinal transducin have been identified as MAR-associated antigens to date. To identify additional antigens potentially involved in the pathogenesis of MAR, we screened a retina cDNA phage library for reactivity with antibodies in the sera from 9 patients with MAR or subclinical MAR using the serological analysis of recombinantly expressed clones (SEREX) approach. Six sera from melanoma patients without evidence of MAR and 10 sera from healthy donors served as controls. Mitofilin and titin were identified as antigens against which antibodies were found exclusively in sera of MAR patients, but not in the sera of MM patients without MAR or healthy donors. This is the first study to demonstrate that titin is highly expressed from retinal tissue and melanoma. The fact that none of the MAR-associated antigens detected to date by their capacity to elicit a humoral immune response is located on the cell surface questions a major pathogenetic role of the respective antibodies and suggests that cellular, rather than humoral mechanisms are operative in the primary immune attack against the retina in MAR.     

Expression of melanoma-associated antigens in human dendritic cells pulsed with an interleukin-2 gene encoded vaccinia melanoma oncolysate (rIL-2VMO)

Dendritic cells (DCs) possess the unique abilities to initiate a primary immune response and to present antigens to na?ve T lymphocytes. Recently, there has been a rapidly growing interest in the use of DCs in active specific immunotherapy (ASI) for the treatment of patients with cancer. In the present study, we determined the ability of DCs to express Melanoma-Associated Antigens (MAAs) from a polyvalent Melanoma Vaccine (DC-MelVac; Patent #11221/5) developed in our facility. The vaccine consists of a recombinant IL-2 gene-encoded vaccinia melanoma oncolysate (rIL-2VMO) derived from an established human melanoma cell line. Our results show that r-IL2VMO-pulsed DCs express MAAs presented by the Mel-2 melanoma cell line oncolysate used in this study. We believe that these promising results will prove useful as an active specific immunotherapeutic agent for patients with Stage III melanoma.     

Metabolism of benzo[a]pyrene by human melanocytes in culture

Benzo[a]pyrene (B[a]P) is a ubiquitous environmental pollutant and known skin carcinogen. In the present study, in vitro addition of [3H]B[a]P to normal human melanocytes in culture, isolated from adult human skin, resulted in the metabolism of [3H]B[a]P both intracellularly and extracellularly. HPLC analysis showed that [3H]B[a]P-9,10- and 7,8-diol were the major intracellular and extracellular metabolites followed by 3,6-quinone, 9-hydroxy and 3-hydroxy metabolites. Significant amounts of the [3H]B[a]P metabolites were found to be present in the sonicated cell suspension and culture medium as the glucuronide and sulfate conjugates. In total 37.3% of the [3H]B[a]P added in the culture medium was metabolized by melanocytes, of which 21.1% was quantified as the intracellular and 16.2% as the extracellular metabolites. Our data show that human melanocytes are capable of metabolizing B[a]P.     

Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model

Immune-based treatments for central nervous system gliomas have traditionally lagged behind those of more immunogenic tumors such as melanoma. The relative paucity of defined glioma-associated antigens that can be targeted by the immune system may partially account for this situation. Antigens present on melanomas have been extensively characterized, both in humans and in murine preclinical models. Melanocytes and astrocytes are both derived embryologically from the neural ectoderm. Their neoplastic counterparts, malignant melanomas and gliomas, have been shown in humans to share common antigens at the RNA level. However, little is known concerning whether gliomas can be targeted by immune-based strategies that prime T cells to epitopes from melanoma-associated antigens (MAAs). In this study, we provide evidence that two common murine glioma cell lines (GL26 and GL261) express the melanoma antigens gp100 and tyrosinase-related protein 2 (TRP-2). To understand the immunogenicity of murine gliomas to CD8(+) T cells, we examined the ability of a MAA-specific CTL cell line to lyse the glioma cells, as well as the in vivo expansion of MAA-specific CD8(+) T cells in animals harboring gliomas. Both glioma cell lines were lysed by a human gp100-specific CTL cell line in vitro. Mice harboring s.c. GL26 gliomas possessed TRP-2-specific CD8(+) T cells, providing further evidence that these gliomas express the protein products in the context of MHC class I. Furthermore, MAA peptide-pulsed dendritic cells could prime T cells that specifically recognize GL26 glioma cells in vitro. Lastly, mice that were prevaccinated with human gp100 and TRP-2 peptide-pulsed dendritic cells had significantly extended survival when challenged with tumor cells in the brain, resulting in >50% long-term survival. These results suggest that shared MAAs on gliomas can be targeted immunotherapeutically, pointing the way to a new potential treatment option for patients with malignant gliomas.     

Identification of melanoma-associated antigens using fixed tissue screening of antibodies

Early culture supernatants from hybridomas that were obtained through fusions of mouse myeloma cells with lymphocytes of melanoma-immunized mice were screened for their reactivity with a paraffin-embedded cell block of a melanoma cell line, using a biotin:avidin immunoperoxidase procedure. Eleven monoclonal antibodies were derived that define several new melanoma-associated antigens. The antigens include a neutral glycolipid, gangliosides, membrane-associated proteins, cytosolic proteins, and strongly secreted proteins. These antibodies, which detect antigens that withstand tissue fixation and embedding procedures, were tested for reactivity in fixed cell lines, as well as in melanoma biopsies. These antibodies may provide powerful tools in diagnostic studies of human malignant melanoma biopsy material.     

Cell surface antigens of melanocytes and melanoma

One major focus of cancer immunology is the question of tumour-specific antigens, the existence of which has yet to be proven. The prime candidates for antigens that can be considered tumour-specific are the class 1 unique antigens that have been serologically defined on human malignant melanomas by antibodies from the tumour-bearing host. In addition to these antigens, intensive immunological, biochemical and genetic analyses of melanoma have permitted a rudimentary classification of other surface antigens expressed by this tumour type. Cell-surface antigens of melanoma can be grouped into three general classes: restricted antigens (i.e. antigens which are expressed by melanomas and astrocytomas) many of which are differentiation markers characterizing cells of neuroectodermal origin; antigens with intermediate distribution (i.e. antigens which are present on some cell tumour types but not on others and which show a limited distribution on normal tissues and cells); and antigens with broad distribution (i.e. antigens expressed by most human cells either malignant or normal). The detailed knowledge of the surface antigens (i.e. differentiation antigens and class 1 unique antigens) of melanoma cells has permitted a rational and coherent approach to assessing the possibility of immunological control of malignant melanoma in the clinic.     

Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo: Implications for tumor vaccines with melanoma-associated antigens

Peptide epitopes derived from differentiation antigens of the melanocyte lineage have been identified in human melanomas and normal cultured melanocytes as targets for MHC-restricted cytotoxic T lymphocytes (CTL). Characterization of multiple CTL-defined antigenic determinants and the presence of corresponding precursor CTL open perspectives for the development of antigen-based vaccines. In the present study, we determined the CTL reactivity against melanoma-associated peptides derived from Melan A/MART-I, tyrosinase and gp100/Pme117 in 10 HLA-A2* melanoma patients and 10 healthy individuals. Then, we examined the immunological effects and toxicity of intradermal inoculation of synthetic melanoma-associated peptides. Six patients with advanced melanoma received weekly intradermal injections of 6 melanoma-associated peptides and the influenza matrix peptide as a control for 4 consecutive weeks. DTH reactions were observed in 5/6 patients at the injection sites of the tyrosinase signal peptide and of the influenza matrix peptide. No toxic side effects were observed. Changes in CTL reactivity after peptide vaccination were assessed by an MLPC assay for each peptide. Generation of peptide-specific CTL was documented against Melan A/MART-I-derived peptide epitopes, the tyrosinase signal peptide and the influenza matrix peptide after vaccination. A decreasing CTL response against the internal tyrosinase peptide was documented in 1 patient through the course of vaccination and a decrease in DTH reactions. No major tumor regressions were observed. Two patients with rapidly progressive disease before vaccination have shown disease stabilization since vaccinations started. In conclusion, our results demonstrate that peptide alone injected intradermally may generate antigen-specific DTH reactions and an increase of antigen-specific CTL reactivity. © 1996 Wiley-Liss, Inc.     

Differentiation and tumorigenicity of human malignant melanocytes in relation to their culture conditions

The effects of variations in the concentrations of L-cystine (Cys), L-methionine (Met), and L-glutamine (Glu) on the establishment of melanocyte cell lines obtained from a primary tumor and its metastasis in the same patient were studied. The special role of Glu was also studied in 4 lymph node metastases from other patients. Differentiation in vitro was dependent on the culture conditions, as assessed by morphologic and biochemical studies. Karyologic expression, doubling time, cloning efficiency, and tumorigenicity in nude BALB/c mice varied widely among the cell lines. Cys was an indispensable amino acid and Glu was not. Met and Glu were implicated in melanogenesis. From these observations arose the question of the accuracy of comparative results, concerning differentiation and tumorigenicity, that had been collected for cell lines obtained under different culture conditions.     

黑色素瘤相关抗原家族在细胞生命活动中的作用

迄今为止,黑色素瘤相关抗原家族(melanoma-associated antigens,MAGEs)已经发现了几十种基因,可分为Ⅰ类和Ⅱ类两个亚类。其中属于癌/睾丸抗原的Ⅰ类MAGE家族基因只在肿瘤细胞和生殖细胞中表达,其中部分抗原或多肽已经在多种肿瘤中进行免疫治疗的临床试验,并取得了较好的临床疗效评价。尽管对于MAGE家族基因在细胞生命活动中的作用还知之较少,但人们已经注意到MAGE家族基因在胚胎发育、生殖细胞发生、细胞凋亡等生命活动中发挥着重要的生理或病理作用。有理由推测Ⅰ类MAGE家族基因在胚胎阶段表达并发挥重要作用后,被基因甲基化等机制灭活,一旦这些基因再次被激活,机体可能发生肿瘤,由这些基因编码的蛋白可被机体免疫系统识别并受到攻击,因此,Ⅰ类MAGE可能在某些肿瘤的免疫监视中起重要作用。本文即对MAGE家族的基因种类及生物功能进行综述。