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Insulin-Like Growth Factor II Is Involved in the Proliferation Control of Medulloblastoma and Its Cerebellar Precursor Cells
Ist Teil von
The American journal of pathology, 2005-04, Vol.166 (4), p.1153-1162
Ort / Verlag
Bethesda, MD: Elsevier Inc
Erscheinungsjahr
2005
Link zum Volltext
Quelle
EZB-FREE-00999 freely available EZB journals
Beschreibungen/Notizen
Medulloblastomas (MBs), the most frequent malignant brain tumors of childhood, presumably originate from cerebellar neural precursor cells. An essential fetal mitogen involved in the pathogenesis of different embryonal tumors is insulin-like growth factor II (IGF-II). We screened human MB biopsies of the classic (CMB) and desmoplastic (DMB) variants for
IGF2
transcripts of the four
IGF2
promoters. We found
IGF2
transcription from the imprinted promoter P3 to be significantly increased in the desmoplastic variant compared to the classic subgroup. This was not a result of loss of imprinting of
IGF2
in desmoplastic tumors. We next examined the interaction of IGF-II and Sonic hedgehog (Shh), which serves as a critical mitogen for cerebellar granule cell precursors (GCPs) in the external granule cell layer from which DMBs are believed to originate. Mutations of genes encoding components of the Shh-Patched signaling pathway occur in ∼50% of DMBs. To analyze the effects of IGF-II on Hedgehog signaling, we cultured murine GCP and human MB cells in the presence of Shh and Igf-II. In GCPs, a synergistic effect of Shh and Igf-II on proliferation and
gli1
and
cyclin D1
mRNA expression was found. Igf-II, but not Shh, induced phosphorylation of Akt and its downstream target Gsk-3β. In six of nine human MB cell lines IGF-II displayed a growth-promoting effect that was mediated mainly through the IGF-I receptor. Together, our data point to an important role of IGF-II for the proliferation control of both cerebellar neural precursors and MB cells.