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

Molecular Cancer

Research

Simona Leonardi¹  Simonetta Rebessi¹  Mariateresa Mancuso¹  Vincenzo Di Majo¹  Simonetta Pazzaglia¹  Melissa Santone¹  Anna Saran¹  Mirella Tanori¹  Emanuela Pasquali¹ 

[1] Section of Toxicology and Biomedical Sciences, ENEA CR-Casaccia, Rome, Italy;

关键词: Proliferate Cell Nuclear Antigen;    Medulloblastoma;    Neural Precursor;    Preneoplastic Lesion;    Cerebellar Development;   

DOI  :  10.1186/1476-4598-9-53

 received in 2009-11-23, accepted in 2010-03-09,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMedulloblastoma 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.ResultsTo 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.ConclusionsAs 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.

【 授权许可】

Unknown   
© Tanori et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.