STEM-CELLS OF TERATOCARCINOMAS AND RELATED GERM-CELL TUMORS

Teratocarcinomas are malignant tumors derived from germ cells or early embryonic cells that have undergone malignant transformation. To unde rstand better the histogenesis of teratocarcinomas and related germ ce ll tumors, the process of tumorigenesis and the nature of tumor stem c ells were studied in murine tumor models. Teratocarcinomas were produc ed by grafting early pregastrulation mouse embryos to extrauterine sit es of syngeneic adult hosts. In the adult host many transplanted cells retained their embryonic phenotype. The adult organism could not cont rol proliferation of these ostensibly normal embryonic cells which ass umed the growth properties of malignant tumor cells. This malignancy d eveloped without viral or chemical carcinogenesis and did not entail a ny genetic transformation. Retinoic acid and related morphogens induce d differentiation and inhibited proliferation of teratocarcinoma stem cells. Likewise, teratocarcinoma stem cells inserted into the embryo w ere regulated by the developmental fields in control of proliferation of normal embryonic cells. These data show that in these cells maligna ncy can develop without irreversible genetic changes, that the maligna nt phenotype is reversible, and that proliferation of teratocarcinoma stem cells can be controlled by developmental fields regulating differ entiation of equivalent normal cells. Murine teratocarcinoma derived f rom embryos is a prototype model for studies of epigenetic control of malignancy.