title: 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+/-) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc1+/- 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 approximately 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 potential clinical target.
authors.affiliation: Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Tal
authors.initials: T
authors.lastname: Bachar Raveh
authors.forename: Monique T
authors.initials: MT
authors.lastname: Barakat
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Scott
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D006579:Heterozygote; D017403:In Situ Hybridization; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D007335:Insulin-Like Growth Factor II