Abstract
Most monoclonal antibodies that have been raised to human epithelial tumours bind to only some of the cells in a tumour, showing that tumour cells are very heterogeneous in their expression of antigens. Normal epithelia show the same heterogeneity of antigen expression, as also do cell lines and clones of epithelial cells in culture. It is not related to the mitotic cell cycle. Many, probably most of the antigenic determinants to which the antibodies bind are carbohydrate structures. It is not clear whether variations in antigen expression reflect variations in the differentiated state of the cells or merely variations in the carbohydrate structures on otherwise identical cells, nor is ir clear whether antibodies could be made that bind to all tumour cells by avoiding antibodies to carbohydrate structures. The normal and apparently reversible nature of this heterogeneity of antigen expression conflicts with conventional views that heterogeneity among cells of a tumour is due to permanent genetic change. The heterogeneity within normal clones suggests that cloning is not an adequate way to study heterogeneity in tumour cells. The implications of heterogeneous expression of antigens within tumours for therapeutic and diagnostic application of antibodies are discussed.
Highlights
Most monoclonal antibodies to epithelial tumours stain the cells of a tumour heterogeneously Typically, when a section through a tumour is stained with a monoclonal antibody, some cells are positive while others of apparently identical morphology are negative
Clones have been grown in monolayer culture to see whether they are homogeneous in antigen expression, from both normal breast epithelial cells and breast tumour cell lines
Is there any way round the problem that antigenic heterogeneity poses for the development of magicbullet therapy with monoclonal antibodies other than trying to raise antibodies to homogeneouslyexpressed antigens? If antigen expression correlates with the differentiated state of a cell, a subset of tumour cells expressing a particular antigen may have the greatest capacity for division or metastasis, so that antibodies to that antigen might be adequate for therapy
Summary
Most monoclonal antibodies to epithelial tumours stain the cells of a tumour heterogeneously Typically, when a section through a tumour is stained with a monoclonal antibody, some cells are positive while others of apparently identical morphology are negative. Legend to Colour Plate Examples of heterogeneous antigen expression by tumours, normal epitheliuin and cloned cells in culture For convenience these examples were obtained using the author's monoclonal antibodies, but they are representative of the antibodies in the field. In breast, antibody HMFGI stains about 30% of normal epithelial cells (Arklie et al, 1981) and in colon some antibodies stain cells predominantly in the crypts while others stain cells higher in the crypts and on the luminal face (Daar & Fabre, 1983; Finaq et al, 1982). Antigenic heterogeneity is shown by cells in culture, both in short term cultures of normal cells and in long-established tumour cell lines (Chang & Taylor-Papadimitriou, 1983; Hand et al, 1983; Peterson et al, 1983; Edwards & Brooks, 1984)
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