期刊
CANCER RESEARCH
卷 68, 期 21, 页码 8788-8795出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-2135
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资金
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [F32 CA117775-02, R01 CA088060-05, R01 CA088060-02, R01 CA088060-01A1, T32 CA009151, R01 CA088060, R01 CA088060-04, #RO1 CA 088060, R01 CA088060-03, 5F32CA117775-03, F32 CA117775, F32 CA117775-03] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007365-30, T32 GM007365-32, T32 GM007365-33, T32 GM007365, T32 GM007365-31] Funding Source: Medline
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+/-) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc-1+/-shows distinct steps of progression. Most ptc1+/- mice form clusters of preneoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In similar to 15% 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+/- 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, PZp53(MED). Blocking igf2 signaling inhibited growth of PZp53(MED) cells, implicating igf2 as a a potential clinical target. [Cancer Res 2008;68(21):8788-95]
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