DIFFERENTIATION OF EL4 LYMPHOMA-CELLS BY TUMORAL ENVIRONMENT IS ASSOCIATED WITH INAPPROPRIATE EXPRESSION OF THE LARGE CHONDROITIN SULFATE PROTEOGLYCAN PG-M AND THE TUMOR-ASSOCIATED ANTIGEN HTGP-175

Progression to malignancy of transformed cells involves complex geneti c alterations and aberrant gene expression patterns. While aberrant ge ne expression is often caused by alterations in individual genes, the contribution of the tumoral environment to the triggering of this gene expression is less well established. The stable but heterogeneous exp ression in cultured EL4/13 cells of a novel tumor-associated antigen, designated as HTgp-175, was chosen for the investigation of gene expre ssion during tumor formation. Homogeneously HTgp-175-negative EL4/13 c ells, isolated by cell sorting or obtained by subcloning, acquired HTg p-175 expression as a result of tumor formation. The tumorigenicity of HTgp-175-negative vs. HTgp-175-positive EL4 variants was identical, i ndicating that induction but not selection accounted for the phenotypi c switch from HTgp-175-negative to HTgp-175-positive. Although mutagen esis experiments showed that the protein was not essential for tumor e stablishment, tumor-derived cells showed increased malignancy linking HTgp-175 expression with genetic changes accompanying tumor progressio n. This novel gene expression was not an isolated event, since it was accompanied by ectopic expression of the large chondroitin sulfate pro teoglycan PG-M and of normal differentiation antigens. We conclude tha t signals derived from the tumoral microenvironment contribute signifi cantly to the aberrant gene expression pattern of malignant cells, app arently by fortuitous activation of differentiation processes and caus e expression of novel differentiation antigens as well as of inappropr iate tumor-associated and ectopic antigens. (C) 1998 Wiley-Liss, Inc.