A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma
38
Citation
141
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Neuroblastoma is the most common extra-cranial solid tumor in children, representing approximately 8% of all malignant childhood tumors and 15% of pediatric cancer-related deaths. Recent sequencing and transcriptomics studies have demonstrated the RAS-MAPK pathway’s contribution to the development and progression of neuroblastoma. This review compiles up-to-date evidence of this pathway’s involvement in neuroblastoma. We discuss the RAS-MAPK pathway’s general functioning, the clinical implications of its deregulation in neuroblastoma, and current promising therapeutics targeting proteins involved in signaling.Keywords:
Childhood Cancer
Ganglioside
Expression (computer science)
Cite
Citations (38)
Cite
Citations (1)
Neuroblastoma is a pediatric malignant tumor of the postganglionic sympathetic nervous system that usually develops in the adrenal gland or in nonadrenal abdominal or thoracic sites.[1] It is the most common malignancy in infants and the most common extracranial solid tumor of childhood, with approximately 650 cases diagnosed annually in the United States.[2] The dramatic age-related survival differences among neuroblastoma patients with a similar tumor stage emphasize the heterogeneity of neuroblastoma pathobiology. Early research efforts to understand the pathobiology of neuroblastoma[3-5] and the significant progress made in neuroblastoma molecular biology[6] have informed the clinical treatment of neuroblastoma.
Solid tumor
Cite
Citations (1)
Abstract MYCN amplification strongly predicts adverse outcome of neuroblastoma. However, the significance of MYCN expression in the clinical and biological behavior of neuroblastoma has been unclear. To address this question, we first examined the expression of MYCN in combination with TrkA (a favorable prognostic indicator of neuroblastoma) in 91 primary neuroblastoma by quantitative reverse transcription-PCR and investigated the relationship among patient survival, MYCN, and TrkA expressions. Three subsets of neuroblastoma were defined based on MYCN and TrkA expression. Neuroblastoma expressing the highest level of MYCN but little TrkA were MYCN-amplified cases, which had a 5-year survival of 9.3%. Interestingly, MYCN and TrkA expression showed a linear correlation (r = 0.5664, P < 0.00005) in neuroblastoma lacking MYCN amplification, and the 5-year survival of neuroblastoma patients with low MYCN and low TrkA expressions was 63.7%, whereas those with high expression of both had a 5-year survival of 88.1% (P < 0.00005). This nonlinear distribution of disease outcome relative to MYCN expression in neuroblastoma explains why MYCN expression is not predictive of neuroblastoma disease outcome by dichotomous division of the neuroblastoma cohort. However, high-level MYCN expression is associated with favorable outcome in neuroblastoma lacking MYCN amplification. Furthermore, forced expression of MYCN significantly suppresses growth of neuroblastoma cells lacking MYCN amplification by inducing apoptosis and enhancing favorable neuroblastoma gene expression. Collectively, these data suggest that high-level MYCN expression in neuroblastoma lacking MYCN amplification results in a benign phenotype. Thus, the high MYCN expression confers the opposite biological consequence in neuroblastoma, depending on whether or not MYCN is amplified. (Cancer Res 2006; 66(5): 2826-33)
N-Myc
Cite
Citations (87)
The excessive activation of extracellular signal-regulated kinase(ERK) signaling pathway,which is a significant feature of rheumatoid arthritic(RA) arthropathy,plays an important role in the process of synoviocyte dysfunction and destruction of cartilage and bone.Understanding the pathomechanism of ERK signaling in RA provides a new target for developing new drug and therapeutic strategy.This review summarizes the current knowledge of the activation,regulation and function of ERK pathway,and also analyzes the role of this signaling transduction in the destruction of joints and the pathogenesis of RA.
Pathogenesis
Cite
Citations (0)
At present,most studies suggest that activation of ERK signaling pathway can promote cell proliferation and JNK signaling pathway are closely related with apoptosis.They are also involved in the pathophysiology change process of many diseases.JNK signal transduction pathway is closely related with neurodegenerative disease or other neurological diseases.ERK signal transduction pathway may be the main mechanism of tumorgenesis and invasiveness,which is also involved in the generation of pains.ERK intracellular localization may be closely related with neuro denaturation.
Hes3 signaling axis
Cite
Citations (0)
The prognosis of mediastinal neuroblastoma has been reported to be better than for other neuroblastomas. The reason for this is however not clear. Furthermore, a comparison between mediastinal neuroblastoma and the other neuroblastomas has been rarely reported so far. In this study, the characteristics of mediastinal neuroblastoma (84 cases) are investigated and compared with those of other neuroblastomas (440 cases). Regarding clinical factors, the age distribution and the rate of cases detected at mass screening were similar in both groups. According to Evan's staging system, the rates of early stage (I, II) were 62% in the mediastinal neuroblastoma and 38% in the other neuroblastomas (p<0.001). Regarding the biological prognostic factors, a favorable histology based on Shimada's classification was found in 100% (35/35) of the mediastinal neuroblastoma cases and in 85% (112/132) of the other neuroblastoma cases (p<0.05). With regard to N-myc amplification, all of the examined 42 cases in mediastinal neuroblastoma had a N-copy number of less than 10 copies, while 32 of the examined 263 cases (12%) in the other neuroblastomas had an amplification of N-myc of more than 10 copies (p<0.05). The 5-year survival rates were 78% in the mediastinal neuroblastoma and 59% in the other neuroblastomas, respectively. Of the cases who underwent an incomplete resection of primary tumors in localized neuroblastoma, the 5-year survival rate of the mediastinal neuroblastoma cases was significantly more favorable than that of the other neuroblastomas. The majority of mediastinal neuroblastoma cases showed an early stage and favorable prognostic factors. It is likely that the clinical and biological prognostic factors of the tumor are therefore more closely correlated with the outcome of mediastinal neuroblastoma rather than the degree of the surgical resection. Regarding the treatment for mediastinal neuroblastoma, it is most important to evaluate the biology of the tumor after surgical resection.
Histology
Mediastinal tumor
Cite
Citations (39)
1. A genomic amplification of N-myc of neuroblastoma was frequently observed in patients in the advanced stage of the disease, in those with the tumor originating from the suprarenal region, and in those with a histologically undifferentiated neuroblastoma. Thus, N-myc may be one of the most pertinent prognostic factors of neuroblastoma in patients over one year of age. 2. The neuroblastoma patient with 1-10 copies of N-myc responded to aggressive multidisciplinary therapy, even those over one year of age. 3. Rapid invasion and progression of the tumor was evident in children with more than 10 copies of N-myc. 4. N-myc amplification may correlate with immaturity of catecholamine metabolism of neuroblastoma.
N-Myc
Cite
Citations (8)
Extracellular signal-regulated kinase (ERK) signaling pathway is one of the mitogen-activated protein kinase (MAPK) signal transduction pathways. This pathway is known as pivotal in many signaling networks that govern proliferation, differentiation and cell survival. The ERK signaling pathway comprises positive and negative feedback loops, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. In this paper, we attempt to model the ERK pathway by considering both of the positive and negative feedback mechanisms based on Michaelis-Menten kinetics. In addition, we propose a fraction ratio model based on the mass action law. We first develop a mathematical model of the ERK pathway with fraction ratios. Secondly, we analyze the dynamical properties of the fraction ratio model based on simulation studies. Furthermore, we propose a concept of an inhibitor, catalyst, and substrate (ICS) controller which regulates the inhibitor, catalyst, and substrate concentrations of the ERK signal transduction pathway. The ICS controller can be designed through dynamical analysis of the ERK signaling transduction pathway within limited concentration ranges.
Cite
Citations (0)
Abstract Background Genetic 1p deletion is reported in 30% of all neuroblastoma and is associated with the unfavorable prognosis of neuroblastoma. The expressions and prognosis of 1p candidate genes in neuroblastoma are unclear. Methods Public neuroblastoma cohorts were obtained for secondary analysis. The prognosis of 1p candidate genes in neuroblastoma was determined using Kaplan-Meier and cox regression analysis. The prediction of the nomogram model was determined using timeROC. Results First, we confirmed the bad prognosis of 1p deletion in neuroblastoma. Moreover, zinc finger protein 436 (ZNF436) located at 1p36 region was down-regulated in 1p deleted neuroblastoma and higher ZNF436 expression was associated with the longer event free survival and overall survival of neuroblastoma. The expression levels of ZNF436 were lower in neuroblastoma patients with MYCN amplification or age at diagnosis ≥ 18months, or with stage 4 neuroblastoma. ZNF436 had robust predictive values of MYCN amplification and overall survival of neuroblastoma. Furthermore, the prognostic significance of ZNF436 in neuroblastoma was independent of MYCN amplification and age of diagnosis. Combinations of ZNF436 with MYCN amplification or age of diagnosis achieved better prognosis. At last, we constructed a nomogram risk model based on age, MYCN amplification and ZNF436. The nomogram model could predict the overall survival of neuroblastoma with high specificity and sensitivity. Conclusions Chromosome 1p36 candidate gene ZNF436 was a prognostic maker of neuroblastoma.
Candidate gene
Cite
Citations (1)