Abstract
Clinical outcomes for high-risk neuroblastoma patients remains poor, with only 40-50% 5-Year overall survival (OS) and <10% long-term survival. The ongoing acquisition of genetic/molecular rearrangements in undifferentiated neural crest cells may endorse neuroblastoma progression. This study recognized the loss of Retinal Degeneration protein 3, RD3 in aggressive neuroblastoma, and identified its influence in better clinical outcomes and defined its novel metastasis suppressor function. The results showed ubiquitous expression of RD3 in healthy tissues, complete-loss and significant TNM-stage association of RD3 in clinical samples. RD3-loss was intrinsically associated with reduced OS, abridged relapse-free survival, aggressive stage etc., in neuroblastoma patient cohorts. RD3 was transcriptionally and translationally regulated in metastatic site-derived aggressive (MSDAC) cells (regardless of CSC status) ex vivo and in tumor manifolds from metastatic sites in reproducible aggressive disease models in vivo. Re-expressing RD3 in MSDACs reverted their metastatic potential both in vitro and in vivo. Conversely muting RD3 in neuroblastoma cells not only heightened invasion/migration but also dictated aggressive disease with metastasis. These results demonstrate the loss of RD3 in high-risk neuroblastoma, its novel, thus-far unrecognized metastasis suppressor function and further imply that RD3-loss may directly relate to tumor aggressiveness and poor clinical outcomes.
Highlights
Neuroblastoma (NB), a predominant tumor of early childhood [1, 2], accounts for 9.1% of pediatric cancer deaths [3,4,5]
Clinical outcome remains poor in patients with high-risk aggressive neuroblastoma, despite intensified multimodal treatment
Considering that nearly half of neuroblastoma patients possess favorable disease with spontaneous regression/maturation, the progression, relapse, and subsequent death in patients with high-risk disease may reflect the ongoing acquisition of genetic manipulations and/or pro-oncogenic adaptations in the undifferentiated tumorigenic neural crest cells that could switch the disease risk status
Summary
Neuroblastoma (NB), a predominant tumor of early childhood [1, 2], accounts for 9.1% of pediatric cancer deaths [3,4,5]. Given the disease’s heterogeneity, resistance, and poor hematological reserve, the likelihood of a cure after relapse of high-risk disease is significantly less, with 5-year OS of 40–50% compared with the >95% OS with low and 90–95% OS with intermediaterisk disease (http://www.cancer.org/cancer/neuroblastoma/ detailedguide/neuroblastoma-survival-rates). Individual Children’s Oncology Group (COG) studies have shown that long term survival rates were poor for patients with stage 4 disease, with only 2% ten-year OS compared with the 38–71% OS for those with low-risk disease [13, 15]. Identifying the crucial molecular targets, defining their orchestration, and understanding the signal transduction flow-through that switches favorable NB to aggressive high-risk NB could lead to the development of an efficient and improved targeted therapeutic strategy and better patient outcomes
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