A significant number of primary tumors in the CNS of children are primitive and embryonal. Their differentiation potential corresponds to the sequential stages of normal neurocytogenesis. They are also of importance because fetal neuroepithelial cells may be a selective target for neoplastic development. The therapeutic response is unpredictable due to poor understanding of their biologic behavior. Tumor arrest or regression has been associated with increased cellular maturation, and substances known to promote differentiation have been proposed as a therapeutic approach. Endogenous substances that may play a role in determining divergent neuroepithelial differentiation in human embryonal CNS tumors have not been studied in this regard. The applicant has studied a highly promising experimental model for neural differentiation in primitive CNS tumors i.e. the neuroepithelilal component of a transplantable mouse teratoma (OTT-6050) which 1) displays a spectrum of divergent neural differentiation corresponding to that of the human tumors 2) can be studied both in vivo and in vitro; 3) has a neural stem cell population capable or repetitive transplantation; and 4) expresses biochemical differentiation consistent with divergent neural cell populations. Serotonin, metabolic enzymes of the biogenic monoamine systems, and cyclic AMP are present in the tumor. Evidence from developing vertebrates and invertebrates suggests that biogenic monoamines may act as early neuroregulators. This research will study the role of monoamines and associated neuropeptides as modulators of early divergent differentiation in CNS tumors using the teratoma model in vivo and in vitro. Studies will focus in particular on serotinin and its membrane receptors because of its predominance among the teratoma monoamines. Morphologic techniques including histochemical fluorescence, immunocytochemistry and autoradiography will be combined with analytical binding kinetic, chromatographic and electrophoretic methods to determine the endogenous levels, synthesis, metabolic relationship with polyamines, interrelationships with monoamine-containing cells, and the time course in development of monoamine neuroregulators in primitive neural cells. An understanding of the mechanisms by which neoplastic neural tissue matures and which might partly be mediated by nonsynaptic neuroregulators may lead to better discrimination of, and thus more precise therapies applicable to, human embryonal CNS tumors.
