p75(NTR) induces apoptosis in medulloblastoma cells.
The classic medulloblastoma (CMB) and the desmoplastic medulloblastoma (DMB) subtypes represent the major medulloblastoma variants. In contrast to CMB, DMB display high levels of the low-affinity nerve growth factor receptor p75(NTR) . Given the reports of a better clinical course of DMB, we hypothesized that p75(NTR) might act as a tumor suppressor in medulloblastomas. In a large set of medulloblastomas, p75(NTR) was screened for mutations, and its mRNA expression and the DNA methylation status of its 5'-region were assessed. p75(NTR) immunostainings were performed in wild-type murine cerebella and medulloblastomas arising in patched heterozygous mice, and murine cerebellar granule cell precursors (GCP) were analyzed in vitro. Medulloblastoma cells engineered to express p75(NTR) were characterized flow cytometrically and morphologically. One CMB displayed a mutation of the p75(NTR) coding sequence. p75(NTR) mRNA levels clearly delineated DMB and CMB; however, CpG island hypermethylation was excluded as the cause of low p75(NTR) expression in CMB. Sonic Hedgehog-treated GCP showed elevated p75(NTR) expression, and strong expression of p75(NTR) was detected in the external granule cell layer of wild-type mice and in murine ptc(±) medulloblastomas. CMB cells overexpressing p75(NTR) displayed a significant increase in apoptosis. In summary, our data link activated Hedgehog signaling in DMB with p75(NTR) expression and characterize p75(NTR) as a biologically relevant inductor of apoptosis in MB.
Küchler
Jan
J
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Hartmann
Wolfgang
W
Waha
Anke
A
Koch
Arend
A
Endl
Elmar
E
Wurst
Peter
P
Kindler
Dagmar
D
Mikeska
Thomas
T
Waha
Andreas
A
Goodyer
Cynthia G
CG
Büttner
Reinhard
R
Schilling
Karl
K
Pietsch
Torsten
T
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015337:Multicenter Studies as Topic; D009474:Neurons; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D053823:Hedgehog Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020800:Receptor, Nerve Growth Factor; C465570:Shh protein, mouse