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 phenotypic properties of medulloblastoma in a paracrine or autocrine manner, 51 pediatric brain tumors including 20 biopsy specimens of these primitive neuroectodermal tumors (PNETs) and 31 other pediatric brain tumors were studied. Immunohistochemistry was used with antibodies to nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3, their cognate high affinity receptors as well as to neuronal and glial markers. TrkA, TrkB, and TrkC were observed in 5 (25%), 8 (40%), and 17 (85%), respectively, of these medulloblastomas while NGF, BDNF, and NT-3 were observed in 6 (30%), 8 (40%), and 3 (15%), respectively, and antibodies to neurofilament (NF) and glial fibrillary acidic proteins (GFAP) stained 16 (80%) and 11 (55%), respectively. TrkA and NGF were not observed in the same biopsy samples, while TrkB and BDNF were co-distributed in 6 of the cases, all of which expressed NF proteins. TrkC and NT-3 were co-distributed in 3 of the medulloblastomas, and these areas overlapped with NF protein-positive tumor cells in all 3 cases. In contrast to medulloblastomas, TrkA and NGF co-distributed in other pediatric brain tumors, and both Trk receptors and their neurotrophins co-distributed with GFAP-positive tumor cells in 13 (42%) of the non-PNET pediatric brain tumors. The absence of medulloblastomas that contain NGF and TrkA is consistent with in vitro data demonstrating that NGF-mediated TrkA signaling induces apoptosis. Finally, this study also suggests that BDNF and NT-3 may act in a paracrine or autocrine manner through TrkB and TrkC receptors, respectively, to induce neuronal differentiation in medulloblastomas.
Tajima
Y
Y
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104-4283, USA.
Molina
R P
RP
Rorke
L B
LB
Kaplan
D R
DR
Radeke
M
M
Feinstein
S C
SC
Lee
V M
VM
Trojanowski
J Q
JQ
D000293:Adolescent; D000951:Antigens, Neoplasm / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D020933:Neurotrophin 3; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
D000951:Antigens, Neoplasm; D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D020933:Neurotrophin 3; D020794:Receptor Protein-Tyrosine Kinases