We use human pediatric tumors and their normal cellular counterparts as model systems to study the molecular events associated with the development of malignant tumors as well as mechanisms mediating HIV- induced neuropathy in children. The focus of the laboratory is pediatric peripheral neuroectodermal tumors including neuroblastoma and the Ewing's sarcoma family of tumors (ESFT). Since neuroblastoma (NB) can be induced to differentiate in vitro, it is an excellent system in which to study the molecular mechanisms regulating growth and differentiation in tumor cells. Our current focus is to: l) identify chemicals and biologic response modifiers that control cell growth and/or induce differentiation in tumor cells; 2) use recombinant DNA technology to identify the molecular mechanisms mediating the signal transduction pathways; and 3) clone the genes important for the regulation of these processes. Once critical genes involved in regulation of neuroectodermal cell growth and differentiation have been identified, we are able to use a normal human fetal olfactory neuroblast cell line that grows and can be induced to differentiate in vitro to address questions regarding the ability of dysregulation of these genes to alter development or tumorigenicity. Past studies have contributed to clinical protocols utilizing retinoic acid and tumor infiltrating lymphocyte therapy protocols utilizing interferon gamma in pediatric tumors. The ability of NB to be induced into normal neuronal cells and our development of a normal human fetal olfactory neuroblast cell line that can be induced to differentiate, serve as in vitro models to study HIV infection of neuronal cells, and effects of HIV infected monocytes and glial cells on normal neuronal development and physiology. Ultimately, our goal is to develop new strategies and novel therapeutics based on understanding the specific alterations in pediatric malignancies and related diseases.
