EXPRESSION OF TRKA CDNA IN NEUROBLASTOMAS MEDIATES DIFFERENTIATION IN-VITRO AND IN-VIVO

The human trkA cDNA was transfected into a malignant human neuroblasto ma (NB) cell line (HTLA230) to investigate its role in NB growth and d ifferentiation. This cell line lacks expression of both endogenous trk A and gp75NGRF genes. Transfectants expressing the trkA mRNA and surfa ce-bound receptors transcriptionally activate immediate-early genes (c -fos, c-jun, and jun-B) following nerve growth factor (NGF) stimulatio n. NGF treatment induces growth arrest as well as down-regulation of t he amplified N-myc oncogene. Genes selectively expressed in mature neu rons (SCG-10, ret proto-oncogene, GAP-43, etc.) are transcriptionally activated, and neurite outgrowth further demonstrates differentiation of transfectants following NGF stimulation. trkA-expressing NB cells r emain tumorigenic in nude mice; however, subcutaneous treatment of tum or-bearing mice with NGF induces Schwannian and neuronal cell differen tiation similar to the induction seen in human ganglioneuroblastomas. Thus, trkA expression in HTLA230 cells is sufficient to generate a fun ctional NGF receptor complex that leads to growth-arrested and differe ntiated NB cells in vitro and in vivo in the presence of NGF. Hence, N GF may play a crucial role in NB cell differentiation and regression i n vivo.