Abstract
Neuroblastoma (NB) is one of the most common malignant solid tumors in childhood, which derives from the sympathoadrenal lineage of the neural crest and exhibits extremely heterogeneous biological and clinical behaviors. The infant patients frequently undergo spontaneous regression even with metastatic disease, whereas the patients of more than one year of age who suffer from disseminated disease have a poor outcome despite intensive multimodal treatment. Spontaneous regression in favorable NBs has been proposed to be triggered by nerve growth factor (NGF) deficiency in the tumor with NGF dependency for survival, while aggressive NBs have defective apoptotic machinery which enables the tumor cells to evade apoptosis and confers the resistance to treatment. This paper reviews the molecules and pathways that have been recently identified to be involved in apoptotic cell death in NB and discusses their potential prospects for developing more effective therapeutic strategies against aggressive NB.
Highlights
Neuroblastoma (NB) is an embryonic malignancy in childhood, which originates from precursor cells of the peripheral nervous system and usually arises in tissues of the sympathetic nervous system, typically in the adrenal medulla or paraspinal ganglia
Considering the following facts (i) the mutation of p53 is rare in primary NBs; (ii) p53 is induced and p53-dependent apoptotic pathway is activated in response to chemotherapeutic agents in NB murine models [56] as well as NB cell lines, and (iii) exogenous expression of tyrosine kinase receptor A (TrkA) induces p53mediated apoptosis even in the NB cells with MYCN amplification, which is inhibited by p53 inactivation [57], p53 should be of functional importance and contribute to apoptotic cell death in favorable NB
These findings argue that BMCC1 might play a role in nerve growth factor (NGF) deficiency-induced neuronal death and contribute at least in part to both developing sympathetic Programmed cell death (PCD) and spontaneous regression of NB
Summary
Neuroblastoma (NB) is an embryonic malignancy in childhood, which originates from precursor cells of the peripheral (sympathetic) nervous system and usually arises in tissues of the sympathetic nervous system, typically in the adrenal medulla or paraspinal ganglia. The patients of more than one year of age who suffer from disseminated diseases at diagnosis have a poor outcome despite intensive multimodal treatment [2]. This extreme clinical heterogeneity reflects the complexity of genetic and genomic events related to the development and progression of the disease. Most of these still experience aggressive growth and relapse due to acquirement of resistance to treatment This indicates that apoptotic signaling is a pivotal mechanism that is effectively activated in infant patients to lead to an excellent prognosis but is defective in high-risk NBs causing a fatal outcome. A better and deeper understanding of the molecules and pathways that control apoptotic cell death in NB will expectedly provide new insights into developing more effective therapeutic strategies against aggressive NB
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