Suppression of tumorigenicity of the PA-1 human teratocarcinoma cell line.

Abstract

Teratocarcinomas are tumors that develop spontaneously in the gonads, and usually contain a rapidly dividing undifferentiated stem-cell population. I have used microcell fusion to introduce individually tagged human chromosomes into the PA-1 human teratocarcinoma cell line. Introduction of human chromosome 4 caused a change of cell morphology in culture and suppressed PA-1 tumorigenicity in nude mice, while addition of portions of either chromosome 7 or 12 had no effect on the cell phenotype. The PA-1 cell line regained its tumorigenicity when the tagged chromosome 4 was lost under negative selection. Tumors were noted in the test period after two out of twelve injections of PA-1 harbouring an additional copy of chromosome 4. One tumor derived cell line had lost the complete tagged chromosome while the other had lost portions of the tagged chromosome (4p11-15.3 and q31.1). I concluded that there is a putative tumor suppressor gene on human chromosome 4 whose expression interferes with the tumorigenicity of PA-1 cells, and that this gene maps to the portion of chromosome 4 lost from the tumor-derived cell line. Differential display of mRNAs from PA-1-derived cell lines revealed that at least two genes, the immunoglobulin heavy chain binding protein (BiP gene) and a novel transcript, are over-expressed as a result of the introduction of chromosome 4 into PA-1. Coincident with the loss of tumorigenicity after introduction of chromosome 4, was an increase in the retinoic acid-induced differentiation of the cell line. Retinoic acid is a potent morphogen and has been implicated in development and differentiation in mammalian systems. Not only did the addition of the tagged chromosome 4 to PA-1 cause an increase in differentiation potential, it also caused an increase in the induction of both retinoic acid receptor-$\alpha$ and HOX1F gene expression. This implies that the increase in retinoid acid-induced differentiation in PA-1-derived cells occurs through a pathway involving retinoic acid receptor-$\alpha .$ Thus, the gene(s) mapping to 4p1.1-15.3 or q31.1 is not only responsible for the suppression of tumorigenicity of PA-1, but it also increases the differentiation potential of the cells.