This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Perturbations in the normal differentiation process during neural crest development can lead to development of tumors such as neuroblastoma (NB), a fatal childhood cancer. Treatment options for children with advanced NB remain limited as NB biology is not well understood. We and others have identified one enzyme called dipeptidyl peptidase (DPPIV) that sits on cell surface and degrades cancer-promoting peptides. Our work has shown that DPPIV is present in normal neural cells while absent in NB cells, suggesting that DPPIV loss contributes to tumor development. Indeed we have demonstrated that restoration of DPPIV in NB cells reverses them towards normal neurons leading to their death, thus suppressing their tumor forming ability. NB cells produces excess levels of Notch receptor 3 and basic FGF that promote tumor growth and survival. Our current studies using gene expression profiles and western blot analysis show that restoration of DPPIV in NB cells decreases levels of Notch3 and the bFGF leading to NB cell differentiation and death. Inhibition of Notch3 and bFGF signaling using RNA interference and pharmacological inhibitors also leads to NB cell death, further demonstrating the importance of blocking Notch3 and bFGF function to suppress NB growth and development. Furthermore, our initial studies show that DPPIV expression is associated with onset of mature differentiated neurons as seen in developing mouse embryos. Overall, our studies not only contribute to the better understanding of NB biology but also provide new insights for developing improved therapeutic approaches to disrupt signals that promote tumor growth and metastasis.
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