Search

Neuroblastoma is the most common extracranial solid tumor in children and comprises one-tenth of all childhood cancer deaths. The current clinical therapy for this deadly disease is multimodal, involving an induction phase with alternating regimens of high-dose chemotherapeutic drugs and load reduction surgery; a consolidation phase with more intensive chemotherapy, radiotherapy, and stem cell transplant; and a maintenance phase with immunotherapy and immune-activating cytokine treatment. Despite such intensive treatment, children with neuroblastoma have unacceptable life quality and survival, warranting preventive measures to regulate the cellular functions that orchestrate tumor progression, therapy resistance, metastasis, and tumor relapse/recurrence. Globally, active efforts are underway to identify novel chemopreventive agents, define their mechanism(s) of action, and assess their clinical benefit. Some chemoprevention strategies (e.g., retinoids, difluoromethylornithine) have already been adopted clinically as part of maintenance phase therapy. Several agents are in the pipeline, while many others are in preclinical characterization. Here we review the classes of chemopreventive agents investigated for neuroblastoma, including cellular events targeted, mode(s) of action, and the level of development. Our review: (i) highlights the pressing need for new and improved chemopreventive strategies for progressive neuroblastoma; (ii) lists the emerging classes of chemopreventive agents for neuroblastoma; and (iii) recognizes the relevance of targeting dynamically evolving hallmark functions of tumor evolution (e.g., survival, differentiation, lineage transformation). With recent gains in the understanding of tumor evolution processes and preclinical and clinical efforts, it is our strong opinion that effective chemopreventive strategies for aggressive neuroblastoma are a near reality., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

Neuroblastoma (NB) is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths. This mortality rate has been attributed to the > 50% frequency of relapse despite intensive, multimodal clinical therapy in patients with progressive NB. Given the disease's heterogeneity and developed resistance, attaining a cure after relapse of progressive NB is highly challenging. A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells (CSCs). In this review, we present the current understanding of NB-CSCs, their intrinsic role in tumorigenesis, their function in disease progression, and their influence on acquired therapy resistance and tumor evolution. In particular, this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB, the function of pre-existing CSCs in NB progression and therapy response, the formation and influence of induced CSCs (iCSCs) in drug resistance and tumor evolution, and the development of a CSC-targeted therapeutic approach., Competing Interests: DECLARATIONS Conflicts of interest All authors declared that there are no conflicts of interest.

Neuroblastoma (NB) deriving from neural crest cells is the most common extra-cranial solid cancer at infancy. NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body. Clinically, NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance. MicroRNAs (miRNAs, miRs) are small (19-22 nt in length) non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling, growth, differentiation, death, stemness, and maintenance. Consequently, the function of miRs in tumorigenesis, progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution, therapy resistance, and poor clinical outcomes. Over the last two decades, much attention has been devoted to understanding the functional roles of miRs in NB biology. This review focuses on highlighting the important implications of miRs within the context of NB disease progression, particularly miRs' influences on NB disease evolution and therapy resistance. In this review, we discuss the functions of both the "oncomiRs" and "tumor suppressor miRs" in NB progression/therapy resistance. These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance., Competing Interests: DECLARATIONS Conflicts of interest All authors declared that there are no conflicts of interest.