Insulin-Like Growth Factor II Is Involved in the Proliferation Control of Medulloblastoma and Its Cerebellar Precursor Cells

Hartmann, Wolfgang; Koch, Arend; Brune, Hendrik; Waha, Anke; Schüller, Ulrich; Dani, Indra; Denkhaus, Dorota; Langmann, W.; Bode, Udo; Wiestler, Otmar D.; Schilling, Karl; Pietsch, Torsten

doi:10.1016/s0002-9440(10)62335-8

Cited by 106 publications

(106 citation statements)

References 41 publications

(45 reference statements)

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“…Shh secretion by Purkinje cells drives proliferation of granule neuron precursors (CGNPs) during development of the cerebellum, and activating mutations in this pathway (for example by inactivating the Shh-antagonist PATCHED1) are associated with the desmoplastic subtype of medulloblastoma. Activating mutations in PIK3CA have been observed in medulloblastoma (Broderick et al, 2004) and PI3K/Akt signaling enhanced the proliferative effects of Shh in these cells (Hartmann et al, 2005b), in addition to increasing tumor incidence in mouse models (Rao et al, 2004). Moreover, a recent report showed loss of Pten in CGNPs, together with Shh expression, also increased medulloblastoma incidence in mice, confirming that the PI3K pathway can contribute to tumorigenesis in this pediatric malignant brain tumor (Hambardzumyan et al, 2008).…”

Section: Pi3k Pathway Involvement In Brain Tumorsmentioning

confidence: 75%

PTEN signaling in brain: neuropathology and tumorigenesis

2008

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Section: Pi3k Pathway Involvement In Brain Tumorsmentioning

confidence: 75%

PTEN signaling in brain: neuropathology and tumorigenesis

2008

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“…This group of tumors is associated with inactivating mutations of the PTCH tumor suppressor gene, activating mutations of its interaction partners, and an activation of the Hedgehog-Patched signaling pathway (2 -4, 22, 23). Recent data have shown that PI3K/ AKT signaling enhances the effects of Hedgehog in these tumors and their cerebellar precursors, and that it may represent an indispensable precondition for the molecular realization of the Hedgehog signal (21,24,25). In agreement with this finding, retroviral co-overexpression of Shh and activated Akt in cerebellar neural progenitors of the mouse newborn cerebellum significantly increased the incidence of tumors compared with the incidence of tumors induced by Shh alone (7).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3′-Kinase/AKT Signaling Is Activated in Medulloblastoma Cell Proliferation and Is Associated with Reduced Expression of PTEN

Hartmann¹,

Digon-Söntgerath²,

Koch³

et al. 2006

Clinical Cancer Research

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Purpose: Medulloblastomas represent the most frequent malignant brain tumors of childhood.They are supposed to originate from cerebellar neural precursor cells. Recently, it has been shown that Sonic Hedgehog^induced formation of medulloblastoma in an animal model is significantly enhanced by activation of the phosphatidylinositol 3 ¶-kinase (PI3K) signaling pathway. Experimental Design: To examine a role for PI3K/AKT signaling in the molecular pathogenesis of human medulloblastoma, we did an immunohistochemical study of the expression of Ser 473 -phosphorylated (p)-AKT protein in 22 medulloblastoma samples: All samples displayed p-AKT expression. To investigate if an activated PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five human medulloblastoma cell lines with increasing concentrations of the PI3K inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The antiproliferative effect could be antagonized by overexpressing constitutively active AKT. As the activation of PI3K/AKT signaling may be associated with alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to frequent allelic losses in medulloblastoma, we screened PTEN for mutations and mRNA expression. Results: Proliferation of all of the medulloblastoma cell lines was dependent on PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss was detected in 16% of the cases. One medulloblastoma cell line was found to carry a truncating mutation in the PTEN coding sequence. Even more important, PTEN mRNA and protein levels were found to be significantly lower in medulloblastomas compared with normal cerebellar tissue of different developmental stages. Reduction of PTEN expression was found to be associated with PTEN promoter hypermethylation in 50% of the tumor samples. Conclusions: We conclude that activation of the PI3K/AKT pathway constitutes an important step in the molecular pathogenesis of medulloblastoma and that dysregulation of PTEN may play a significant role in this context.

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“…Interestingly, another recent report (26) shows that IGF2-positive medulloblastoma cells in situ are restricted to a subpopulation that displays intense Ki-67 staining and that cultured medulloblastoma-derived cells and cerebellar neuronal precursors are growth-stimulated by IGF2. Thus, IGF2 may serve as an effective mitogen to promote growth of both medulloblastomas and GBMs, two forms of central nervous system malignancies both hypothesized to arise from neural stem and/or precursor cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma

Soroceanu

Kharbanda

Chen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Amplification or overexpression of growth factor receptors is a frequent occurrence in malignant gliomas. Using both expression profiling and in situ hybridization, we identified insulin-like growth factor 2 (IGF2) as a marker for a subset of glioblastomas (GBMs) that lack amplification or overexpression of EGF receptor. Among 165 primary high-grade astrocytomas, 13% of grade IV tumors and 2% of grade III tumors expressed IGF2 mRNA levels >50-fold the sample population median. IGF2-overexpressing tumors frequently displayed PTEN loss, were highly proliferative, exhibited strong staining for phospho-Akt, and belonged to a subclass of GBMs characterized by poor survival. Using a serum-free culture system, we discovered that IGF2 can substitute for EGF to support the growth of GBMderived neurospheres. The growth-promoting effects of IGF2 were mediated by the insulin-like growth factor receptor 1 and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of phosphoinositide 3-kinase that shows genomic gains in some highly proliferative GBM cases. PIK3R3 knockdown inhibited IGF2-induced growth of GBM-derived neurospheres. The current results provide evidence that the IGF2-PIK3R3 signaling axis is involved in promoting the growth of a subclass of highly aggressive human GBMs that lack EGF receptor amplification. Our data underscore the importance of the phosphoinositide 3-kinase/Akt pathway for growth of high-grade gliomas and suggest that multiple molecular alterations that activate this signaling cascade may promote tumorigenesis. Further, these findings highlight the parallels between growth factors or receptors that are overexpressed in GBMs and those that support in vitro growth of tumor-derived stem-like cells.astrocytoma ͉ brain tumor ͉ expression profiling ͉ glioma ͉ gliomagenesis

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Insulin-Like Growth Factor II Is Involved in the Proliferation Control of Medulloblastoma and Its Cerebellar Precursor Cells

Abstract: Medulloblastomas (MBs),

Cited by 106 publications

References 41 publications

PTEN signaling in brain: neuropathology and tumorigenesis

PTEN signaling in brain: neuropathology and tumorigenesis

Phosphatidylinositol 3′-Kinase/AKT Signaling Is Activated in Medulloblastoma Cell Proliferation and Is Associated with Reduced Expression of PTEN

Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma

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