NEUROTROPHINS AND NEURONAL VERSUS GLIAL DIFFERENTIATION IN MEDULLOBLASTOMAS AND OTHER PEDIATRIC BRAIN-TUMORS

Medulloblastomas are highly malignant and poorly understood childhood neoplasms. To determine if neurotrophins might influence the phenotypi c properties of medulloblastoma in a paracrine or autocrine manner, 51 pediatric brain tumors including 20 biopsy specimens of these primiti ve neuroectodermal tumors (PNETs) and 31 other pediatric brain tumors were studied. Immunohistochemistry was used with antibodies to nerve g rowth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3 , their cognate high affinity receptors as well as to neuronal and gli al markers. TrkA, TrkB, and TrkC were observed in 5 (25%), 8 (40%), an d 17 (85%), respectively, of these medulloblastomas while NGF, BDNF, a nd NT-3 were observed in 6 (30%), 8 (40%), and 3 (15%), respectively, and antibodies to neurofilament (NF) and glial fibrillary acidic prote ins (GFAP) stained 16 (80%) and 11 (55%), respectively. TrkA and NGF w ere not observed in the same biopsy samples, while TrkB and BDNF were codistributed in 6 of the cases, all of which expressed NF proteins. T rkC and NT-3 were co-distributed in 3 of the medulloblastomas, and the se areas overlapped with NF protein-positive tumor cells in all 3 case s. In contrast to medulloblastomas, TrkA and NGF co-distributed in oth er pediatric brain tumors, and both Trk receptors and their neurotroph ins co-distributed with GFAP-positive tumor cells in 13 (42%) of the n on-PNET pediatric brain tumors. The absence of medulloblastomas that c ontain NGF and TrkA is consistent with in vitro data demonstrating tha t NGF-mediated TrkA signaling induces apoptosis. Finally, this study a lso suggests that BDNF and NT-3 may act in a paracrine or autocrine ma nner through TrkB and TrkC receptors, respectively, to induce neuronal differentiation in medulloblastomas.