Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice

Abstract

Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in neural progenitor cells of the cerebellum induces MBs in mice. The incomplete penetrance of tumor formation in mice, coupled with the low frequency of mutations in Shh/ Ptc pathway genes in human tumors, suggests that other signaling molecules cooperate with Shh to enhance MB formation. We modeled the ability of insulin-like growth factor (IGF) signaling to induce MB using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell-type-specific manner. We used RCAS retroviral vectors to target expression of Shh, IGF2, and activated Akt to nestin-expressing neural progenitors in the cerebella of newborn mice. The incidence of Shhinduced tumor formation (15%) was enhanced by coexpression with IGF2 (39%) and Akt (48%). Neither IGF2 nor Akt caused tumors when expressed independently. The induced tumors showed upregulated expression of insulin receptor substrate 1 and phosphorylated forms of IGF1 receptor and Akt, mimicking activated IGF signaling found in human MBs. These results indicate that combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis.

PTEN signaling in brain: neuropathology and tumorigenesis

“…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).…”

IGFBP-2 - taking the lead in growth, metabolism and cancer

“…Although synergism between the IGF1R and Hh signalling has been implicated in another cancer type (Rao et al 2004), the expression and action of IGFBP-2 in BCC appears to be IGF-independent in nature (Villani et al 2010) .…”

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

“…Many mouse models have elegantly established that CD133 þ ventricular zone stem cells are distinct from Math1 þ external granule layer cells (Lee et al, 2005Gibson et al, 2010), and strong evidence suggests that although non-hedgehog pathway medulloblastoma may originate from the former, the Shh subtype of medulloblastoma likely originates from the latter (Rao et al, 2004;Schuller et al, 2008;Read et al, 2009;Sutter et al, 2010). Our application of BTIC culture conditions to human primary medulloblastomas and medulloblastoma cell lines allows for the enrichment of both stem and progenitor cell populations that exist within tumor spheres.…”