Insulin-like Growth Factor 2 Is Required for Progression to Advanced Medulloblastoma in patched1 Heterozygous Mice

Abstract

Medulloblastoma (MB) can arise in the cerebellum due to genetic activation of the Sonic Hedgehog (Shh) signaling pathway. During normal cerebellum development, Shh spurs the proliferation of granule neuron precursors (GNP), the precursor cells of MB. Mutations in the Shh receptor gene patched1 (ptc1+/À) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc1+/À shows distinct steps of progression. Most ptc1+/À mice form clusters of preneoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In f15% of mice, these preneoplastic cells will become fast-growing, lethal tumors. It was previously shown that the loss of function of insulin-like growth factor 2 (igf2) suppresses MB formation in ptc1+/À mice. We found that igf2 is not expressed in preneoplastic lesions but is induced as these lesions progress to more advanced MB tumors. Igf2 is not required for formation of preneoplastic lesions but is necessary for progression to advanced tumors. Exogenous Igf2 protein promoted proliferation of MB precursor cells (GNP) and a MB cell line, PZp53MED . Blocking igf2 signaling inhibited growth of PZp53 MED cells, implicating igf2 as a potential clinical target. [Cancer Res 2008;68(21):8788-95]

LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro

“…The early increase in Igf2 mRNA parallels the increase in neurons: both occur prior to the time at which let-7 levels normally rise, and both require the two conserved RNA-binding domains of LIN28. Igf2 has a documented role in the formation of neural tumors and promotes neurogenesis (Corcoran et al, 2008;Mori et al, 2001;Sim et al, 2006). Thus, the importance of Igf2 in neurogenesis is consistent with it being involved in the increase in neurons observed with constitutive LIN28.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Several hedgehog target genes are growth factors or growth factor receptors (Xie, 2008b), such as IGF-2, VEGF and PDGFRa. Recent data further show the significance of IGF signaling for Hh-mediated carcinogenesis (Corcoran et al, 2008;Parathath et al, 2008). Gene expression analysis in keratinocytes indicates that EGF and hedgehog have synergistic effects on gene expression of MEK/ERK/JUN (Kasper et al, 2006;Schnidar et al, 2009).…”

Gene Expression Profiling of the Hedgehog Signaling Pathway in Human Meningiomas

“…Several genes are regulated by the Hh signal: (a) MTSS1 (metastasis suppressor 1)-a regulator of actin filaments assembly-which is expressed in embryonic tissues including the developing central nervous system and downregulated or missing in metastatic cancer cell lines (16); (b) the Forkhead family of transcription factors, which are associated with cell growth and proliferation, such as FOXE1, FOXA2 and FOXM1 (a regulator of cell-cycle geneexpression), and all have been found in human cancers (17)(18)(19); (c) SPP1 (osteopontin) and OSF (periostin)-secreted extracellular matrix-associated proteinswhich have a crucial role in cell adhesion, prevention of apoptosis, invasion and migration (20,21); (d) IGF2 (insulinlike growth factor 2) and CCND2, a cyclin required for cell cycle G 1 /S transition, both of which are overexpressed in tumors (22,23); (e) PTHR1, a parathyroid hormone receptor, which is overexpressed in osteosarcoma and bone metastases of other tumors (24).…”