Tumor antigens

Tumor imaging depends on the presence of an antigen that is either exclusively expressed on the tumor or at least has an appreciable difference in its amount and/or distribution between the tumor and normal tissues. Tumor antigens are usually separated into two categories: tumor-specific antigens and tumor-associated antigens. The former are expressed only in tumors and are never detectable in normal tissues. They are often unique to a single tumor and, thus, not shared by tumors of different individuals. Theoretically, an ideal tumor-specific antigen would be that associated with mutational change(s) of an oncogene or a tumor suppressor gene that caused the malignant transformation. Since peptides produced by enzymatic processing of intracellular proteins arc displayed on major histocompatibility complex (MHC) class I molecules, T lymphocytes may recognize a mutated peptide associated with the oncogenesis. How professional antigen-presenting cells that are capable of activating naive T cells capture tumor-specific antigen peptides, which are produced only by the tumor cells but not by the antigen-presenting cells, is still unclear. In any case, most of these tumor-specific antigens are recognized by T cells, and it is generally difficult to imagine that antibodies reacting with an intracellular oncogene product accumulate in a small lesion filled with fully viable tumor cells.

On the other hand, tumor-associated antigens are expressed at an inappropriately high level in tumor cells, whereas the expression of the same antigen in normal tissues is very low or strongly restricted to a certain stage or site in tissue development. Many of these tumor-associated antigens are detectable with heterologous and sometimes autologous antibodies. Notable examples arc carbohydrate antigens including gangliosides and blood group antigens, carcino-embryonic antigen (CEA), «-fetoprotein, mucins, cell surface receptor-like molecules, and some hormones and enzymes. Among them, antibodies reacting with CEA, carbohydrate antigens and mucins have been most extensively studied for use in tumor imaging.

CEA is a cell surface glycoprotein of 180 kDa, and its expression is most frequently associated with adenocarcinomas of colon, breast and lung. CA19-9 or sialyl Lea is a typical tumor-associated carbohydrate antigen. This modified blood group antigen is highly expressed on most gastrointestinal carcinomas including adenocarcinomas of pancreas, colon and stomach. Mucins are extremely high molecular weight glycoproteins that are abundantly-expressed on the surface of breast, colon, pancreas, ovary and lung adenocarcinomas. Since the presence of mucins in normal tissues is confined to the apical surface of the ductal epithelial cells and in the ductal lumen, they are usually sequestered from the immune sytem. The unpolar and excessive nature of mucin production in tumor cells leads to the production of antibodies. Many monoclonal antibodies reacting with human tumor-associated mucins are generated by immunizing mice with tumor tissues. Human chorionic gonadotropin (hCG) secreted by choriocarcinoma was the first tumor antigen used for targeting.

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