Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice.
Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in neural progenitor cells of the cerebellum induces MBs in mice. The incomplete penetrance of tumor formation in mice, coupled with the low frequency of mutations in Shh/Ptc pathway genes in human tumors, suggests that other signaling molecules cooperate with Shh to enhance MB formation. We modeled the ability of insulin-like growth factor (IGF) signaling to induce MB using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell-type-specific manner. We used RCAS retroviral vectors to target expression of Shh, IGF2, and activated Akt to nestin-expressing neural progenitors in the cerebella of newborn mice. The incidence of Shh-induced tumor formation (15%) was enhanced by coexpression with IGF2 (39%) and Akt (48%). Neither IGF2 nor Akt caused tumors when expressed independently. The induced tumors showed upregulated expression of insulin receptor substrate 1 and phosphorylated forms of IGF1 receptor and Akt, mimicking activated IGF signaling found in human MBs. These results indicate that combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis.
Rao
Ganesh
G
Department of Neurosurgery, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132-2303, USA.
Pedone
Carolyn A
CA
Del Valle
Luis
L
Reiss
Krzysztof
K
Holland
Eric C
EC
Fults
Daniel W
DW
D000818:Animals; D002460:Cell Line; D002528:Cerebellar Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000166:cytology*; D002645:Chickens; D005822:Genetic Vectors; D053823:Hedgehog Proteins; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D008527:Medulloblastoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D064231:Nestin; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D053823:Hedgehog Proteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011518:Proto-Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D007335:Insulin-Like Growth Factor II; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt