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Type III TGF-? receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

ABSTRACT: Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-? receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, T?RIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. T?RIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. T?RIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. T?RIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for T?RIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.

SUBMITTER: Knelson EH

PROVIDER: S-EPMC3809791 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Knelson Erik H EH Gaviglio Angela L AL Tewari Alok K AK Armstrong Michael B MB Mythreye Karthikeyan K Blobe Gerard C GC

The Journal of clinical investigation 20131101 11

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-β receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse out ...[more]

PMID: 24216509

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Project description:Tumor microenvironment contains various components including cancer cells, tumor vessels, and cancer associated fibroblasts (CAFs), comprising of tumor-promoting myofibroblasts and tumor-suppressing fibroblasts. Multiple lines of evidence indicated that transforming growth factor-β (TGF-β) induces the formation of myofibroblasts and other types of mesenchymal (non-myofibroblastic) cells from endothelial cells. Recent reports showed that fibroblast growth factor 2 (FGF2) modulates TGF-β-induced mesenchymal transition of endothelial cells, but the molecular mechanisms regarding the signals that control the transcriptional networks during the formation of different groups of fibroblasts remain largely unclear. Here, we studied the roles of FGF2 during the regulation of TGF-β-induced mesenchymal transition of tumor endothelial cells (TECs). We demonstrated that auto/paracrine FGF signals in TECs inhibit TGF-β-induced endothelial-to-myofibroblast transition (End-MyoT), leading to suppressed formation of contractile myofibroblast cells, but on the other hand can also collaborate with TGF-β in promoting the formation of active fibroblastic cells which have migratory and proliferative properties. FGF2 modulated TGF-β-induced formation of myofibroblastic and non-myofibroblastic cells from TECs via transcriptional regulation of the array of various mesenchymal markers and growth factors. Furthermore, we observed that TECs treated with TGF-β were more competent in promoting in vivo tumor growth than TECs treated with TGF-β and FGF2. Mechanistically, we showed that Elk1 mediated this FGF2-induced inhibition of End-MyoT via inhibition of TGF-β-induced transcriptional activation of α-SMA promoter by myocardin-related transcription factor (MRTF)-A. Our data suggest that TGF-β and FGF2 oppose and cooperate with each other during the formation of myofibroblastic and non-myofibroblastic cells from TECs to determine the characteristics of the mesenchymal cells in tumor microenvironment. Identification of marker genes for TGF-β-induced endothelial-to-myofibroblast transition

Dataset Information

Type III TGF-? receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Publications

Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

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