Oncofetal expression of Lex carbohydrate antigens in human colonic adenocarcinomas. Regulation through type 2 core chain synthesis rather than fucosylation.

N Graem,E H Holmes,H Clausen,G K Ostrander

doi:10.1016/s0021-9258(18)60963-9

Abstract

The mechanism of expression of a series of glycolipid antigens carrying the Lex determinant structure, Gal beta 1----4[Fuc alpha 1----3]GlcNAc beta 1----, and characterized by oncofetal expression in fetal colon and colonic adenocarcinomas has been studied in human fetal and adult proximal colon tissue. Results presented from TLC immunostain analysis of neutral glycolipids isolated from normal adult colonic mucosa have indicated the presence of only barely detectable quantities of both an Lex-active glycolipid that co-migrated with III3V3Fuc2nLc6 and its precursor nLc6. These structures were found in large quantities in glycolipid fractions from human adenocarcinoma tumors and human small cell lung carcinoma NCI-H69 cells. In contrast, type 1 chain-based Lea antigen structures were found in both normal mucosa and adenocarcinomas. Analysis of gangliosides of normal colonic mucosa by TLC immunostain indicated the presence of a series of type 2 chain-based gangliosides; however, sialyl-Lex was not detected. The ability of normal colonic mucosa to synthesize type 2 chain core structures was demonstrated by the presence of a beta 1----4 galactosyltransferase activity with Lc3 as an acceptor in an amount equivalent to 60-65% of the total galactosyltransferase activity. An alpha 1----3 fucosyltransferase was also found to be expressed in significant quantity in adult colonic mucosa. Kinetic studies indicated that this is most probably the alpha 1----3/4 fucosyltransferase suggested to be a product of the Lewis gene (Le). Thus, although normal adult colonic mucosa contained the enzymes to synthesize Lex and sialyl-Lex structures, these antigens were not found. Tissue immunofluorescence studies indicated that type 2 chain precursors and the alpha 1----3/4 fucosyltransferase were found in different cell populations in adult proximal colonic mucosa. However, both type 2 chain core structures and their fucosylated derivatives were found to be associated with epithelial cells of fetal colon. These results indicate that oncofetal expression of Lex antigens in fetal colonic epithelium and in adenocarcinomas but not in normal adult mucosa is due to the retrogenetic expression of type 2 chain precursors which are not found in normal adult colonic epithelial cells.

Highlights

The mechanismof expression of a seriesof glycolipid sors which are not found in normal adult colonic epiantigenscarryingthe
The most tures werefound in large quantitieisn glycolipid frac- simple structure is that of lactofucopentaosyl(II1)ceramide tions from human adenocarcinoma tumors andhuman (II13FucnLc,) which wasfound to be rich in lung, gastric, and small cell lung carcinoma NCI-H69 cells
In of gangliosides of normal colonic mucosa by TLC im- addition, glycolipids have been found to carry internal a1-3 munostain indicated the presence of a series of type 2 fucosyl residues on sialylated type 2 chain core structures

Summary

TABLEI Glycolipid structures referred to in this study

Fucal carcinomas is most probably due to regulation of synthesis of type 2 chain precursors. These structures were found not to be expressed in normal adult colonic epithelial cells but highly expressed in bothfetalintestinal epithelia and tumor cell lines. Evidence is presented to indicate that control of expression of type 2 chain core structures may be associated with normal development and that itsinduction in epithelial cells during oncogenesis is most probably the controlling mechanism responsible for formation of all type 2 chain-based tumor-associated antigens which are found to accumulate in human colonic adenocarcinomas

RESULTS

Two enzvme enzvmes

Galactose transferred

DISCUSSION