Developmental and oncogenic effects of insulin-like growth factor-I in Ptc1+/- mouse cerebellum.
BACKGROUND
Medulloblastoma is amongst the most common malignant brain tumors in childhood, arising from neoplastic transformation of granule neuron precursors (GNPs) of the cerebellum via deregulation of pathways involved in cerebellar development. Deregulation of the Sonic hedgehog/Patched1 (Shh/Ptc1) signaling pathway predisposes humans and mice to medulloblastoma. In the brain, insulin-like growth factor (IGF-I) plays a critical role during development as a neurotrophic and neuroprotective factor, and in tumorigenesis, as IGF-I receptor is often activated in medulloblastomas.


RESULTS
To investigate the mechanisms of genetic interactions between Shh and IGF signaling in the cerebellum, we crossed nestin/IGF-I transgenic (IGF-I Tg) mice, in which transgene expression occurs in neuron precursors, with Ptc1+/- knockout mice, a model of medulloblastoma in which cancer develops in a multistage process. The IGF-I transgene produced a marked brain overgrowth, and significantly accelerated tumor development, increasing the frequency of pre-neoplastic lesions as well as full medulloblastomas in Ptc1+/-/IGF-I Tg mice. Mechanistically, tumor promotion by IGF-I mainly affected preneoplastic stages through de novo formation of lesions, while not influencing progression rate to full tumors. We also identified a marked increase in survival and proliferation, and a strong suppression of differentiation in neural precursors.


CONCLUSIONS
As a whole, our findings indicate that IGF-I overexpression in neural precursors leads to brain overgrowth and fosters external granular layer (EGL) proliferative lesions through a mechanism favoring proliferation over terminal differentiation, acting as a landscape for tumor growth. Understanding the molecular events responsible for cerebellum development and their alterations in tumorigenesis is critical for the identification of potential therapeutic targets.
Tanori
Mirella
M
Section of Toxicology and Biomedical Sciences, ENEA CR-Casaccia, Rome, Italy.
Santone
Melissa
M
Mancuso
Mariateresa
M
Pasquali
Emanuela
E
Leonardi
Simona
S
Di Majo
Vincenzo
V
Rebessi
Simonetta
S
Saran
Anna
A
Pazzaglia
Simonetta
S
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D011230:Precancerous Conditions / Q000196:embryology* / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000235:genetics
D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D007334:Insulin-Like Growth Factor I