The transforming growth factor beta (TGF-beta) signaling pathway regulates the development and function of the peripheral nervous system and has a significant role in the pathogenesis of the pediatric cancer, neuroblastoma (NB). TGF-beta ligands have been shown to promote neuritogenesis and neuronal differentiation of NB cells in vitro. The type III TGF-beta receptor (TbetaRIII) is a transmembrane proteoglycan which undergoes ectodomain shedding, releasing a soluble receptor form (sTbetaRIII). TbetaRIII acts as a co-receptor in the TGF-beta signaling pathway, regulating TGF-beta ligand bioavailability to mediate canonical activation of TGF-beta-stimulated transcription factors. TbetaRIII also has TGF-beta signaling-independent roles in regulating cell proliferation, migration and invasion. Decreased TbetaRIII expression has been reported in the progression of several adult cancers and has been associated with advanced-stage NB. Microarray dataset analysis demonstrates a decrease in TbetaRIII expression in malignant NB compared with benign ganglioneuroblastoma and ganglioneuroma. This analysis also reveals that TbetaRIII expression positively correlates with tumor stromal content, which is associated with improved clinical prognosis. Consistent with this result, we observe expression of TbetaRIII in the stroma of NB clinical specimens. In preliminary in vitro data, we demonstrate that restoration of TbetaRIII expression or treatment with sTbetaRIII promotes neuritogenesis and neuronal differentiation in a cell line model of NB. sTbetaRIII released from a Schwannian stromal cell line also has neuritogenic and differentiating effects on neuroblastic cells of the same lineage. While sTbetaRIII has been characterized as an inhibitor of TGF-beta signaling, functioning via ligand sequestration, the ability of sTbetaRIII to mimic the effect o TGF-beta ligands suggests a novel mechanism for sTbetaRIII function. Elucidating the molecular mechanisms directing sTbetaRIII's effects on NB tumor cell differentiation will aid in identifying therapeutic targets for this devastating pediatric cancer. Based on our preliminary data and the defined role of TGF-beta signaling in neuronal differentiation and NB pathogenesis, we hypothesize that sTbetaRIII released by the stroma promotes neuronal differentiation via canonical TGF-beta signaling to inhibit NB invasiveness.
The goal of my research is to determine whether the soluble type III TGF-beta receptor, when released from the tumor stroma, increases neuroblastoma cell differentiation to suppress tumor invasiveness, and the mechanism by which this occurs. Elucidating this mechanism will aid in identifying therapeutic targets for this devastating pediatric cancer.
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