Altered Glycolipid and Glycoprotein Antigens

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Most human and experimental tumors express higher than normal levels or abnormal forms of surface glycoproteins and glycolipids, which may be diagnostic markers and targets for therapy. These altered molecules include gangliosides, blood group antigens, and mucins. Some aspects of the malignant phenotype of tumors, including tissue invasion and metastatic behavior, may reflect altered cell surface properties that result from abnormal glycolipid and glycoprotein synthesis. Many antibodies have been raised in animals that recognize the carbohydrate groups or peptide cores of these molecules. Although most of the epitopes recognized by these antibodies are not specifically expressed on tumors, they are present at higher levels on cancer cells than on normal cells. This class of tumor-associated antigen is a target for cancer therapy with specific antibodies.

Gangliosides, including GM2, GD2, and GD3, are glycolipids expressed at high levels in neuroblastomas, melanomas, and many sarcomas. Because of the tumor-selective expression of these molecules, they are an attractive target for tumor-specific therapies such as antibody therapy. Clinical trials of anti-ganglioside antibodies and immunization with ganglioside vaccines are under way in patients with melanoma. Mucins are high-molecular-weight glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide. Tumors often have dysregulated expression of the enzymes that synthesize these carbohydrate side chains, which leads to the appearance of tumor-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core. Several mucins have been the focus of diagnostic and therapeutic studies, including CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on breast carcinomas. Unlike many mucins, MUC-1 is an integral membrane protein that is normally expressed only on the apical surface of breast ductal epithelium, a site that is relatively sequestered from the immune system. In ductal carcinomas of the breast, however, the molecule is expressed in an nonpolarized fashion and contains new, tumor-specific carbohydrate and peptide epitopes detectable by mouse monoclonal antibodies. The peptide epitopes induce both antibody and T cell responses in cancer patients, and efforts are under way to develop vaccines containing immunogenic forms of MUC-1 epitopes.

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