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Intracranial Orthotopic Allografting of Medulloblastoma Cells in Immunocompromised Mice
Published on: October 3, 2010
p75(NTR) induces apoptosis in medulloblastoma cells
Jan Küchler1, Wolfgang Hartmann, Anke Waha
1Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Abstract:
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.
Insights
The low-affinity nerve growth factor receptor p75(NTR) acts as a tumor suppressor in medulloblastomas. Activated Hedgehog signaling in desmoplastic medulloblastoma correlates with p75(NTR) expression, inducing apoptosis.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Genetics
Background:
- Medulloblastoma (MB) has major variants: classic (CMB) and desmoplastic (DMB).
- Desmoplastic medulloblastoma (DMB) exhibits higher p75(NTR) levels than CMB.
- p75(NTR) is a low-affinity nerve growth factor receptor implicated in neuronal development and apoptosis.
Purpose of the Study:
- To investigate the role of p75(NTR) as a potential tumor suppressor in medulloblastoma.
- To correlate p75(NTR) expression with medulloblastoma subtypes and clinical course.
- To elucidate the regulatory mechanisms of p75(NTR) expression in medulloblastoma.
Main Methods:
- Screening for p75(NTR) mutations in medulloblastoma samples.
- Assessing p75(NTR) mRNA expression and DNA methylation status.
- Immunohistochemistry in murine models and in vitro analysis of cerebellar granule cell precursors (GCPs).
- Flow cytometry and morphological characterization of MB cells engineered to express p75(NTR).
Main Results:
- One CMB case showed a p75(NTR) coding sequence mutation.
- p75(NTR) mRNA levels differentiated DMB from CMB.
- CpG island hypermethylation was ruled out as a cause for low p75(NTR) expression in CMB.
- Sonic Hedgehog pathway activation in GCPs elevated p75(NTR) expression.
- Overexpression of p75(NTR) in CMB cells significantly increased apoptosis.
Conclusions:
- p75(NTR) expression is linked to activated Hedgehog signaling in DMB.
- p75(NTR) functions as a biologically relevant inducer of apoptosis in medulloblastoma.
- p75(NTR) may serve as a therapeutic target for medulloblastoma treatment.
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