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Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

Developmental and oncogenic effects of Insulin-like Growth Factor-I in Ptc1+/- mouse cerebellum

Authors: Mirella Tanori, Melissa Santone, Mariateresa Mancuso, Emanuela Pasquali, Simona Leonardi, Vincenzo Di Majo, Simonetta Rebessi, Anna Saran, Simonetta Pazzaglia

Published in: Molecular Cancer | Issue 1/2010

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Abstract

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.
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Metadata
Title
Developmental and oncogenic effects of Insulin-like Growth Factor-I in Ptc1+/- mouse cerebellum
Authors
Mirella Tanori
Melissa Santone
Mariateresa Mancuso
Emanuela Pasquali
Simona Leonardi
Vincenzo Di Majo
Simonetta Rebessi
Anna Saran
Simonetta Pazzaglia
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-53

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