Neuroblastoma is one of the most common solid tumours of early childhood usually found in babies or young children. The disease originates in the adrenal medulla or other sites of sympathetic nervous tissue. The most common site is the abdomen (near the adrenal gland) but can also be found in the chest, neck, pelvis, or other sites. Most patients have widespread disease at diagnosis.
This page contains links to information specifically related to Neuroblastoma, other relevant resources are availible via the Main Menu of Children's Cancer Web.
CNCF CNCF is a non-profit national organization committed to finding a cure for neuroblastoma through research, education, awareness and advocacy. Founded in 2000 by parents. The site includes news, details of events information for newly diagnosed, in-treatment and post-treatment.
A charity which helps children and families affected by neuroblastoma in the UK by providing financial assistance for children's clinical treatment; supporting families affected by the disease and raise money to fund neuroblastoma research.
NANT A group of institutions throughout North America, committed to working together on clinical trials of novel approaches to treating high-risk neuroblastoma. The Website includes information about neuroblastoma and about the NANT clinical trials.
The Neuroblastoma Society is a charity, formed in 1982, which raises funds for medical research into improving both diagnosis and treatment of the disease. The Society also offers an opportunity for parents to give each other mutual help, support and comfort.
PubMed Central search for free-access publications about Neuroblastoma MeSH term: Neuroblastoma US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
An international conference held every 2 years, alternating between Europe and the USA. These meetings provide for an exchange of information among investigators studying neuroblastoma biology, diagnosis, prognosis, and therapy.
NANT A group of institutions throughout North America, committed to working together on clinical trials of novel approaches to treating high-risk neuroblastoma. The Website includes information about neuroblastoma and about the NANT clinical trials.
SIOP International Society of Paediatric Oncology European Neuroblastoma Research Network. This aims to optimise the use of European pre-existing infrastructures in the individual countries and to improve their consistency and complementarity on a European level. The pooling of data will contribute to harmonised standard procedures and integrate the research efforts to reach a critical mass.
SEER, National Cancer Institute Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
This list of publications is regularly updated (Source: PubMed).
Currò M, Montalto AS, Impellizzeri P, et al. CO(2) pneumoperitoneum induces in vitro hypoxic response culminating in apoptosis of human neuroblastoma cells. J Biol Regul Homeost Agents. 2014 Jul-Sep; 28(3):497-506 [PubMed] Related Publications
The ablative role of minimally invasive surgery (MIS) in neuroblastoma (NB) is still controversial due to the possible CO₂ pneumoperitoneum side-effects on tumor aggressiveness. It is known that CO₂ produces hypoxic condition with changes in tumor microenvironment influencing cell functions. Here we investigated whether CO₂ exposure affects the transcription factor HIF-1α and the apoptotic signalling pathway in SH-SY5Y NB cells. SH-SY5Y cells were exposed to a pressure of 15 mmHg CO₂ (100%) for 4 h (T0) and then moved to normal condition for 24 h (T₂₄). In control and CO₂ -exposed cells, we analyzed the mRNA levels and DNA binding activity of HIF-1α. We also evaluated the proliferative activity and cell viability as well as caspase-9/3 cleavage and nuclear fragmentation. A significant increase in HIF- 1α activation was observed in SH-SY5Y cells exposed to CO₂ compared to control cells. CO₂ treatment also decreased the proliferation rate and the percentage of viable cells. In addition, the expression and cleavage of caspase-9 and -3 were significantly increased in NB cells exposed to CO₂. These data correlated with apoptotic feature observed in CO₂ -treated NB cells. Our findings show that CO₂ -induced hypoxic condition exerts cytotoxic effects on NB cells by eliciting mitochondrial apoptotic pathway and thereby improving the understanding of the possible clinical impact of CO₂ pneumoperitoneum on NB behaviour.
Squillaci S Olfactory neuroblastoma with focal ganglioneuroblastic differentiation: a case report with literature review. Pathologica. 2014; 106(2):61-6 [PubMed] Related Publications
Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumour, with clearly defined histologic and immunohistochemical features, that typically arises in the superior nasal cavity. Although the classical clinicopathological features leave little room for misinterpretation, the wide variability in this tumour, including occasional divergent differentiation, may cause diagnostic difficulty. Herein, an unusual case of ONB with focal ganglioneuroblastic differentiation in an 81-year-old woman arising from the anterior ethmoid, filling the upper portion of the left nasal cavity and sparing the sinus cavities, is described. Histologically, the tumour was composed of atypical monotonous round cells that were positive for NSE, CD56, chromogranin, synaptophysin, neurofilament and calretinin and exhibited an irregular lobulated and nested growth pattern and sparse mitotic figures (3 to 4 mitoses per 10 HPF). Focally, the histology changed to ganglioneuroblastic differentiation consisting of large ganglion and spindle cells, positively staining for S-100, GFAP, CD99, neurofilament, calretinin, chromogranin and synaptophysin. Neuroblastomas, occurring in the nasal cavity, in analogy to other sites, tend to have an aggressive biologic behaviour and can histologically mimic other undifferentiated malignant neoplasms of the sinonasal tract. Differential diagnostic problems are discussed; a comprehensive review of the literature has also been performed with a focus on survival.
Rahman MH, Ramanathan M, Sankar V Preparation, characterization and in vitro cytotoxicity assay of curcumin loaded solid lipid nanoparticle in IMR32 neuroblastoma cell line. Pak J Pharm Sci. 2014; 27(5):1281-5 [PubMed] Related Publications
Curcumin (diferuloylmethane) possesses low bioavailability due to its poor solubility, permeability and rapid metabolism. Solid Lipid Nanoparticle of curcumin was prepared by high-speed homogenization technique. Stearic acid was used as a lipid, tween 80 as surfactant and various co surfactants were used for the preparation of SLN. The prepared SLN was characterized using zeta sizer, TEM analysis and the average particle size was found to be in the range of 80 nm - 200nm. The entrapment efficiency of the SLN was ~58 to 85%. The characteristic FTIR peaks suggest that the stearic acid is compatible with curcumin. MTT assay was performed on the optimized formulation and the results are indicative that curcumin SLN showed better cytotoxicity in low dose while compared to plain curcumin. The developed Cu-SLN can find its better place in the anticancer therapy.
Gustafson WC, Meyerowitz JG, Nekritz EA, et al. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell. 2014; 26(3):414-27 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity.
Solari V, Borriello L, Turcatel G, et al. MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cell survival. Cancer Res. 2014; 74(21):5999-6009 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Vo KT, Matthay KK, Neuhaus J, et al. Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project. J Clin Oncol. 2014; 32(28):3169-76 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
PURPOSE: Neuroblastoma (NB) is a heterogeneous tumor arising from sympathetic tissues. The impact of primary tumor site in influencing the heterogeneity of NB remains unclear. PATIENTS AND METHODS: Children younger than age 21 years diagnosed with NB or ganglioneuroblastoma between 1990 and 2002 and with known primary site were identified from the International Neuroblastoma Risk Group database. Data were compared between sites with respect to clinical and biologic features, as well as event-free survival (EFS) and overall survival (OS). RESULTS: Among 8,369 children, 47% had adrenal tumors. All evaluated clinical and biologic variables differed statistically between primary sites. The features that were > 10% discrepant between sites were stage 4 disease, MYCN amplification, elevated ferritin, elevated lactate dehydrogenase, and segmental chromosomal aberrations, all of which were more frequent in adrenal versus nonadrenal tumors (P < .001). Adrenal tumors were more likely than nonadrenal tumors (adjusted odds ratio, 2.09; 95% CI, 1.67 to 2.63; P < .001) and thoracic tumors were less likely than nonthoracic tumors (adjusted odds ratio, 0.20; 95% CI, 0.11 to 0.39; P < .001) to have MYCN amplification after controlling for age, stage, and histologic grade. EFS and OS differed significantly according to the primary site (P < .001 for both comparisons). After controlling for age, MYCN status, and stage, patients with adrenal tumors had higher risk for events (hazard ratio, 1.13 compared with nonadrenal tumors; 95% CI, 1.03 to 1.23; P = .008), and patients with thoracic tumors had lower risk for events (HR, 0.79 compared with nonthoracic; 95% CI, 0.67 to 0.92; P = .003). CONCLUSION: Clinical and biologic features show important differences by NB primary site, with adrenal and thoracic sites associated with inferior and superior survival, respectively. Future studies will need to investigate the biologic origin of these differences.
Yang M, Wang XB, Li J, et al. Surgical treatment of large abdominally involved primary dumbbell tumor in the lumbar region. J Spinal Disord Tech. 2014; 27(7):E268-75 [PubMed] Related Publications
STUDY DESIGN: This was a retrospective clinical study. OBJECTIVE: The aim of this study was to assess the efficacy of a combined anterior and posterior approach, or single-stage posterior extensive approach for resection of large abdominally involved dumbbell tumor in the lumbar region. BACKGROUND: Resection of the large spinal-retroperitoneal involved dumbbell tumor is particularly controversial and challenging because of unique exposure requirements. METHODS: From June 2006 to October 2011, 18 consecutive patients suffering from large dumbbell tumors in the lumbar region were involved. In the initial 8 patients, a combined posterior and anterior surgical approach was applied. The remaining 10 patients were surgically treated with a single posterior extensive approach to excise both the intraspinal and intra-abdominal tumors. Reconstruction with bone or mesh grafts was also performed simultaneously in 3 of the 10 patients in this group. RESULTS: The perioperative period was uneventful for 7 of 8 patients who underwent combined surgery. However, 1 patient encountered right nephrectomy because of a ruptured renal vein and refractory bleeding during anterior tumor exposure. Histopathology revealed the presence of schwannoma (n=4), neurofibroma (n=3), and neuroblastoma (n=1). With the mean of 52 months of follow-up, metastasis occurred in 1 patient with neuroblastoma. In the 10 patients with only the posterior approach, histopathology demonstrated schwannoma (n=5), neurofibroma (n=3), small round cell mesenchymal tumor (n=1), and benign fibrous histiocytoma (n=1). No recurrence was detected at the mean follow-up of 24 months. CONCLUSIONS: The posterior extensive approach is safe and effective to remove the large abdominally involved dumbbell tumors, and also facilitates simultaneously reconstruction of the vertebral body, as compared with the combined posterior and anterior approach.
Schleiermacher G, Janoueix-Lerosey I, Delattre O Recent insights into the biology of neuroblastoma. Int J Cancer. 2014; 135(10):2249-61 [PubMed] Related Publications
Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genome-wide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.
Kasim M, Benko E, Winkelmann A, et al. Shutdown of achaete-scute homolog-1 expression by heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 in hypoxia. J Biol Chem. 2014; 289(39):26973-88 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
The basic helix-loop-helix transcription factor hASH1, encoded by the ASCL1 gene, plays an important role in neurogenesis and tumor development. Recent findings indicate that local oxygen tension is a critical determinant for the progression of neuroblastomas. Here we investigated the molecular mechanisms underlying the oxygen-dependent expression of hASH1 in neuroblastoma cells. Exposure of human neuroblastoma-derived Kelly cells to 1% O2 significantly decreased ASCL1 mRNA and hASH1 protein levels. Using reporter gene assays, we show that the response of hASH1 to hypoxia is mediated mainly by post-transcriptional inhibition via the ASCL1 mRNA 5'- and 3'-UTRs, whereas additional inhibition of the ASCL1 promoter was observed under prolonged hypoxia. By RNA pulldown experiments followed by MALDI/TOF-MS analysis, we identified heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 and hnRNP-R as interactors binding directly to the ASCL1 mRNA 5'- and 3'-UTRs and influencing its expression. We further demonstrate that hnRNP-A2/B1 is a key positive regulator of ASCL1, findings that were also confirmed by analysis of a large compilation of gene expression data. Our data suggest that a prominent down-regulation of hnRNP-A2/B1 during hypoxia is associated with the post-transcriptional suppression of hASH1 synthesis. This novel post-transcriptional mechanism for regulating hASH1 levels will have important implications in neural cell fate development and disease.
Tafavogh S, Catchpoole DR, Kennedy PJ Cellular quantitative analysis of neuroblastoma tumor and splitting overlapping cells. BMC Bioinformatics. 2014; 15:272 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
BACKGROUND: Neuroblastoma Tumor (NT) is one of the most aggressive types of infant cancer. Essential to accurate diagnosis and prognosis is cellular quantitative analysis of the tumor. Counting enormous numbers of cells under an optical microscope is error-prone. There is therefore an urgent demand from pathologists for robust and automated cell counting systems. However, the main challenge in developing these systems is the inability of them to distinguish between overlapping cells and single cells, and to split the overlapping cells. We address this challenge in two stages by: 1) distinguishing overlapping cells from single cells using the morphological differences between them such as area, uniformity of diameters and cell concavity; and 2) splitting overlapping cells into single cells. We propose a novel approach by using the dominant concave regions of cells as markers to identify the overlap region. We then find the initial splitting points at the critical points of the concave regions by decomposing the concave regions into their components such as arcs, chords and edges, and the distance between the components is analyzed using the developed seed growing technique. Lastly, a shortest path determination approach is developed to determine the optimum splitting route between two candidate initial splitting points. RESULTS: We compare the cell counting results of our system with those of a pathologist as the ground-truth. We also compare the system with three state-of-the-art methods, and the results of statistical tests show a significant improvement in the performance of our system compared to state-of-the-art methods. The F-measure obtained by our system is 88.70%. To evaluate the generalizability of our algorithm, we apply it to images of follicular lymphoma, which has similar histological regions to NT. Of the algorithms tested, our algorithm obtains the highest F-measure of 92.79%. CONCLUSION: We develop a novel overlapping cell splitting algorithm to enhance the cellular quantitative analysis of infant neuroblastoma. The performance of the proposed algorithm promises a reliable automated cell counting system for pathology laboratories. Moreover, the high performance obtained by our algorithm for images of follicular lymphoma demonstrates the generalization of the proposed algorithm for cancers with similar histological regions and histological structures.
Han SM, Kim JM, Park KK, et al. Neuroprotective effects of melittin on hydrogen peroxide-induced apoptotic cell death in neuroblastoma SH-SY5Y cells. BMC Complement Altern Med. 2014; 14:286 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
BACKGROUND: Free radicals are involved in neuronal cell death in human neurodegenerative diseases. Since ancient times, honeybee venom has been used in a complementary medicine to treat various diseases and neurologic disorders. Melittin, the main component of honeybee venom, has various biologic effects, including anti-bacterial, anti-viral, and anti-inflammatory activities. METHODS: We investigated the neuroprotective effects of melittin against H2O2-induced apoptosis in the human neuroblastoma cell line SH-SY5Y. The neuroprotective effects of melittin on H2O2-induced apoptosis were investigated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazolium bromide assay, caspase 3 activity, 4,6-diamidino-2-phenylindole staining, a lactate dehydrogenase release assay, Western blots, and reverse transcription-polymerase chain reaction. RESULTS: The H2O2-treated cells had decreased cell viability with apoptotic features and increased production of caspase-3. On the other hand, melittin treatment increased cell viability and decreased apoptotic DNA fragmentation. Melittin attenuated the H2O2-induced decrease in mRNA and protein production of the anti-apoptotic factor Bcl-2. In addition, melittin inhibited both the H2O2-induced mRNA and protein expression of Bax-associated pro-apoptotic factor and caspase-3. CONCLUSIONS: These findings suggest that melittin has potential therapeutic effects as an agent for the prevention of neurodegenerative diseases.
Cangelosi D, Muselli M, Parodi S, et al. Use of Attribute Driven Incremental Discretization and Logic Learning Machine to build a prognostic classifier for neuroblastoma patients. BMC Bioinformatics. 2014; 15 Suppl 5:S4 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
BACKGROUND: Cancer patient's outcome is written, in part, in the gene expression profile of the tumor. We previously identified a 62-probe sets signature (NB-hypo) to identify tissue hypoxia in neuroblastoma tumors and showed that NB-hypo stratified neuroblastoma patients in good and poor outcome 1. It was important to develop a prognostic classifier to cluster patients into risk groups benefiting of defined therapeutic approaches. Novel classification and data discretization approaches can be instrumental for the generation of accurate predictors and robust tools for clinical decision support. We explored the application to gene expression data of Rulex, a novel software suite including the Attribute Driven Incremental Discretization technique for transforming continuous variables into simplified discrete ones and the Logic Learning Machine model for intelligible rule generation. RESULTS: We applied Rulex components to the problem of predicting the outcome of neuroblastoma patients on the bases of 62 probe sets NB-hypo gene expression signature. The resulting classifier consisted in 9 rules utilizing mainly two conditions of the relative expression of 11 probe sets. These rules were very effective predictors, as shown in an independent validation set, demonstrating the validity of the LLM algorithm applied to microarray data and patients' classification. The LLM performed as efficiently as Prediction Analysis of Microarray and Support Vector Machine, and outperformed other learning algorithms such as C4.5. Rulex carried out a feature selection by selecting a new signature (NB-hypo-II) of 11 probe sets that turned out to be the most relevant in predicting outcome among the 62 of the NB-hypo signature. Rules are easily interpretable as they involve only few conditions. CONCLUSIONS: Our findings provided evidence that the application of Rulex to the expression values of NB-hypo signature created a set of accurate, high quality, consistent and interpretable rules for the prediction of neuroblastoma patients' outcome. We identified the Rulex weighted classification as a flexible tool that can support clinical decisions. For these reasons, we consider Rulex to be a useful tool for cancer classification from microarray gene expression data.
Schleiermacher G, Javanmardi N, Bernard V, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014; 32(25):2727-34 [PubMed] Related Publications
PURPOSE: In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. METHODS: We analyzed ALK mutations in 54 paired diagnosis-relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000× deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. RESULTS: All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). CONCLUSION: In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.
Williams P, Wegner E, Ziegler DS Outcomes in multifocal neuroblastoma as part of the neurocristopathy syndrome. Pediatrics. 2014; 134(2):e611-6 [PubMed] Related Publications
The neurocristopathy syndrome occurs because of a germline mutation of the paired-like homeobox 2b (PHOX2B) gene at 4p12, a neurogenesis regulator gene. The result is abnormal neural crest cell development resulting in congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma (NB), which is often multifocal and disseminated in its presentation. Previously, such widespread disease was regarded as highly aggressive and treated either with palliative intent or, conversely, with very intense, high-dose chemotherapy. We now present a patient who had neurocristopathy syndrome who had multifocal NB associated with an underlying germline PHOX2B mutation. He was treated conservatively with surgery and low-dose chemotherapy. After treatment he had extensive residual disease that has continued to mature despite no further treatment. A literature review identified 26 similar patients presenting with multifocal NB as part of the neurocristopathy syndrome. In all cases the NB behaved in an indolent manner with no deaths from tumor reported when patients received appropriate treatment. These provocative findings suggest for the first time that children who have neurocristopathy-associated NB should be treated conservatively, despite the aggressive appearance of their disease.
Sethi K, Lee YH, Daugherty LE, et al. ROHHADNET syndrome presenting as major behavioral changes in a 5-year-old obese girl. Pediatrics. 2014; 134(2):e586-9 [PubMed] Related Publications
Behavioral issues are a frequent problem in the pediatric population. Often, these are evaluated and considered to be psychiatric in origin. We report on a pediatric patient who presented with severe behavioral disturbance and developed organic symptoms including hypoventilation and dysautonomia and who was ultimately diagnosed with ROHHADNET syndrome, a syndrome of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation associated with a neuroendocrine tumor. Autopsy findings revealed novel findings of the syndrome, including hypothalamic encephalitis.
Barnhill LM, Williams RT, Cohen O, et al. High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma. Cancer Res. 2014; 74(14):3753-63 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Neuroblastoma is a pediatric cancer with significant genomic and biologic heterogeneity. p16 and ARF, two important tumor-suppressor genes on chromosome 9p21, are inactivated commonly in most cancers, but paradoxically overexpressed in neuroblastoma. Here, we report that exon γ in p16 is also part of an undescribed long noncoding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single-exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue, but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16, and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced-stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high-risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease.
Lim JY, Kim YS, Kim KM, et al. Β-carotene inhibits neuroblastoma tumorigenesis by regulating cell differentiation and cancer cell stemness. Biochem Biophys Res Commun. 2014; 450(4):1475-80 [PubMed] Related Publications
Neuroblastoma (NB) is the most common extracranial solid cancer in young children and malignant NB cells have been shown to possess cancer stem cell (CSC) characteristics. Thus, the successful elimination of CSCs represents a strategy for developing an effective preventive and chemotherapeutic agent. CSCs are characterized by differentiation and tumorigenicity. β-Carotene (BC) has been associated with many anticancer mechanisms, although the efficacy of BC on CSCs remains unclear. In the present study, the effects of BC on tumor cell differentiation and tumorigenicity was investigated using a xenograft model. Mice were pretreated with BC for 21 days, then received a subcutaneous injection of SK-N-BE(2)C cells. Both tumor incidence and tumor growth were significantly inhibited for mice that received BC supplementation compared to the control group. Treatment with BC has also been shown to induce tumor cell differentiation by up-regulating differentiation markers, such as vimentin, peripherin, and neurofilament. Conversely, BC treatment has been shown to significantly suppress tumor stemness by down-regulating CSC markers such as Oct 3/4 and DLK1. BC treatment also significantly down-regulated HIF1-α expression and its downstream target, vascular endothelial growth factor (VEGF). Taken together, these results suggest that BC is a potential chemotherapeutic reagent for the treatment of NB, and mediates this effect by regulating the differentiation and stemness of CSCs, respectively.
Han X, Gui B, Xiong C, et al. Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development. Mol Cell. 2014; 55(3):482-94 [PubMed] Related Publications
Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.
Li Y, Li W, Zhang JG, et al. Downregulation of tumor suppressor menin by miR-421 promotes proliferation and migration of neuroblastoma. Tumour Biol. 2014; 35(10):10011-7 [PubMed] Related Publications
Neuroblastoma, featured by a high rate of spontaneous remissions, is the most common extra-cranial solid tumor in infants and children. Numerous reports have demonstrated that MicroRNAs (miRNAs) play essential roles in cancer progression, including cell proliferation, apoptosis, invasion, metastasis and angiogenesis. miR-421 functions as an onco-miR in some malignancies. However, its role in neuroblastoma remains poorly understood. In the present study, we found that miR-421 was increased in neuroblastoma tissues compared with matched adjacent normal tissues. Forced overexpression of miR-421 substantially enhanced cell proliferation, cell-cycle progression, migration, and invasion of neuroblastoma cells. At the molecular level, tumor suppressor menin was found to be a target of miR-421. Furthermore, downregulation of menin by small interfering RNA oligos exhibited similar effects with overexpression of miR-421. On the other hand, overexpression of menin partially reversed the proliferative effects of miR-421 in neuroblastoma cells. Collectively, miR-421 may promote neuroblastoma cell growth and motility partially by targeting menin.
Altered dopamine homeostasis plays a key role in the pathogenesis of Parkinson's disease. The generation of reactive oxygen species by spontaneous dopamine oxidation impairs mitochondrial function, causing in turn an enhancement of oxidative stress. Recent findings have highlighted the role of mitochondrial outer membrane proteins in the regulation of the correct disposal of damaged mitochondria. Here, we report the effect of altered dopamine homeostasis on the mitochondrial functionality in human neuroblastoma SH-SY5Y cells, a cellular model widely used to reproduce impaired dopamine homeostasis. We observed that dopamine significantly and relevantly reduces VDAC1 and VDAC2 levels without any change in the mRNA levels. Although mitochondria are depolarized by dopamine and mitochondrial calcium influx is reduced, dysfunctional mitochondria are not removed by mitophagy as it would be expected. Thus, alteration of dopamine homeostasis induces a mitochondrial depolarization not counteracted by the mitophagy quality control. As a consequence, the elimination of VDACs may contribute to the altered mitochondrial disposal in PD pathogenesis, thus enhancing the role of oxidative stress.
Lach B, Joshi SS, Murty N, Huq N Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis. Hum Pathol. 2014; 45(9):1978-81 [PubMed] Related Publications
Merkel cell carcinoma is an aggressive neuroendocrine tumor occasionally demonstrating aberrant differentiation to other epithelial and nonepithelial cell lines. We describe a case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy.
Peeters Y, Van de Velde M, Neyrinck AP, Vermeylen K Approach to one lung ventilation during the surgical resection of an intrathoracic ganglioneuroblastoma in a three-year-old child: a case report and review of the literature. Acta Anaesthesiol Belg. 2014; 65(1):45-9 [PubMed] Related Publications
One lung ventilation (OLV) in children is a challenge and requires creative solutions. A case of OLV with bronchial placement of a fiberscope inspection-guided vascular embolectomy catheter in a three-year-old girl, scheduled for the resection of an intrathoracic tumor through thoracotomy is described. The availability of a broad range of vascular catheters as well as of fiberscope inspection material was decisive in managing the airway intra-operatively. Over the last 20 years, the need for OLV in children has increased, and various methods for performing it have been reported. Knowing all existing strategies in that domain is important to provide optimal perioperative care. In this paper, several methods of OLV in children will be discussed, such as selective endobronchial intubation, types of bronchial blockers, Univent tube, pediatric double lumen tubes, as well as the Marraro double lumen tube.
Inoue S, Setoyama Y, Odaka A Phagocytosis of bafilomycin A1-treated apoptotic neuroblastoma cells by bone marrow-derived dendritic cells initiates a CD8α+ lymphocyte response to neuroblastoma. J Pediatr Hematol Oncol. 2014; 36(5):e290-5 [PubMed] Related Publications
This study aimed to determine whether bafilomycin A1 (Baf-A1), a vacuolar H-ATPase inhibitor, could promote an immune response after the induction of apoptosis in mouse neuroblastoma cells. Mouse neuro-2a cells were cultured in a medium containing Baf-A1, and apoptosis was evaluated by flow cytometry. To examine the influence in the phagocytic cell, CD11b spleen cells or bone marrow-derived dendritic cells (BM-DCs) were cocultured with Baf-A1-treated neuro-2a. Interferon-γ (IFN-γ) production was used as an index of the immune response, and CDDP was used as the negative control. When CD8α cells were cocultured with CD11b cells and Baf-A1-treated neuro-2a cells in the presence of CpG-oligodeoxynucleotide (CpG-ODN) (a toll-like receptor 9 [TLR-9] agonist), CD8α lymphocyte proliferation and secretion of IFN-γ were observed. Phagocytosis of apoptotic cells by BM-DCs was maximal after simultaneous stimulation with CpG-ODN and lipopolysaccharide (LPS; a TLR-4 agonist). IFN-γ secretion was maximal when Baf-A1-treated neuro-2a cells and CD8α lymphocytes were cocultured with BM-DCs and stimulated with CpG-ODN. In contrast, IFN-γ production was not increased when the cells were cultured with LPS. When cells were stimulated with both CpG-ODN and LPS, promotion of IFN-γ production by CpG-ODN was suppressed. Induction of apoptosis by Baf-A1 could possibly enhance antitumor immunity in patients receiving chemotherapy for neuroblastoma. Stimulation of BM-DCs with a TLR-9 agonist could promote antitumor activity after Baf-A1 treatment.
Tan WQ, Chen G, Jia B, Ye M Artemisinin inhibits neuroblastoma proliferation through activation of AHP-activated protein kinase (AMPK) signaling. Pharmazie. 2014; 69(6):468-72 [PubMed] Related Publications
Recent population studies suggest that the use of artemisinin is associated with reduced incidence and improved prognosis of certain cancers. In the current study, we assessed the effect of artemisinin on neuroblastoma cells using SHSY5Y cells. We found that artemisinin inhibited growth and modulated expression of cell-cycle regulators in these cells. Treatment with artemisinin was also associated with activation of AMP kinase and inhibition of mTOR/p70S6K/pS6 signaling in SHSY5Y cells. In addition, inhibition of AMPK signaling reversed impact on the anti-proliferative roles of artemisinin. Taken together, these results provide evidence for a mechanism that may contribute to the antineoplastic effects of artemisinin suggested by recent population studies and justify further work to explore its potential roles in neuroblastoma prevention and treatment.
Gómez-Villafuertes R, Pintor J, Miras-Portugal MT, Gualix J Ectonucleotide pyrophosphatase/phosphodiesterase activity in Neuro-2a neuroblastoma cells: changes in expression associated with neuronal differentiation. J Neurochem. 2014; 131(3):290-302 [PubMed] Related Publications
Neuro-2a (N2a) neuroblastoma cells display an ectoenzymatic hydrolytic activity capable of degrading diadenosine polyphosphates. The Apn A-cleaving activity has been analysed with the use of the fluorogenic compound BODIPY FL guanosine 5'-O-(3-thiotriphosphate) thioester. Hydrolysis of this dinucleotide analogue showed a hyperbolic kinetic with a Km value of 4.9 ± 1.3 μM. Diadenosine pentaphosphate, diadenosine tetraphosphate, diadenosine triphosphate, and the nucleoside monophosphate AMP behaved as an inhibitor of BODIPY FL guanosine 5'-O-(3-thiotriphosphate) thioester extracellular degradation. Ectoenzymatic activity shared the typical characteristics of the ectonucleotide pyrophosphatase/phosphodiesterase family, as hydrolysis reached maximal activity at alkaline pH and was dependent on the presence of divalent cations, being strongly inhibited by EDTA and activated by Zn(2+) ions. Both NPP1 and NPP3 isozymes are expressed in N2a cells, their expression levels substantially changing when cells differentiate into a neuronal-like phenotype. In this sense, it is relevant to point the expression pattern of the NPP3 protein, whose levels were drastically reduced in the differentiated cells, being almost completely absent after 24 h of differentiation. Enzymatic activity assays carried out with differentiated N2a cells showed that NPP1 is the main isozyme involved in the extracellular degradation of dinucleotides in these cells, this enzyme reducing its activity and changing its subcellular location following neuronal differentiation. We described the presence of an ectoenzymatic activity able to hydrolyse diadenosine polyphosphates (ApnA) in N2a cells. This activity displays biochemical features that are typical of the ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) family members, as demonstrated by the use of the fluorogenic compound BODIPY-FL-GTPγS. Both NPP1 and NPP3 ectoenzymes are expressed in N2a cells, their levels dramatically changing when cells differentiate into a neuronal-like phenotype. Activity assays in differentiated cells showed that the ApnA-hydrolytic activity largely depends on the NPP1 isozyme.
Knelson EH, Gaviglio AL, Nee JC, et al. Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth. J Clin Invest. 2014; 124(7):3016-31 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Neuroblastoma prognosis is dependent on both the differentiation state and stromal content of the tumor. Neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here, we identified critical growth-limiting components of the differentiating stroma secretome and designed a potential therapeutic strategy based on their central mechanism of action. We demonstrated that expression of heparan sulfate proteoglycans (HSPGs), including TβRIII, GPC1, GPC3, SDC3, and SDC4, is low in neuroblasts and high in the Schwannian stroma. Evaluation of neuroblastoma patient microarray data revealed an association between TGFBR3, GPC1, and SDC3 expression and improved prognosis. Treatment of neuroblastoma cell lines with soluble HSPGs promoted neuroblast differentiation via FGFR1 and ERK phosphorylation, leading to upregulation of the transcription factor inhibitor of DNA binding 1 (ID1). HSPGs also enhanced FGF2-dependent differentiation, and the anticoagulant heparin had a similar effect, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-desulfated heparin (ODSH) as a differentiating agent, and treatment of orthotopic xenograft models with ODSH suppressed tumor growth and metastasis without anticoagulation. These studies support heparan sulfate signaling intermediates as prognostic and therapeutic neuroblastoma biomarkers and demonstrate that tumor stroma biology can inform the design of targeted molecular therapeutics.
Erickson BP, Tse DT Management of neonatal proptosis: a systematic review. Surv Ophthalmol. 2014 Jul-Aug; 59(4):378-92 [PubMed] Related Publications
Gross proptosis presenting at birth is an uncommon manifestation of a variety of lesions that can compromise vision and result in disfigurement or even loss of life. Notably, many disease entities have different presentations and prognoses in neonates compared to older children. A structured mental framework is essential to an efficient and coordinated response. We present three challenging cases of neonatal proptosis and discuss the clinical presentation and biological behavior of the lesions that are most often implicated.
Chen L, Zhao Y, Halliday GC, et al. Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma. Br J Cancer. 2014; 111(4):716-25 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: A frequent mechanism of acquired multidrug resistance in human cancers is overexpression of ATP-binding cassette transporters such as the Multi-Drug Resistance Protein 1 (MDR-1). Nutlin-3, an MDM2-p53 antagonist, has previously been reported to be a competitive MDR-1 inhibitor. METHODS: This study assessed whether the structurally diverse MDM2-p53 antagonists, MI-63, NDD0005, and RG7388 are also able to modulate MDR-1 function, particularly in p53 mutant neuroblastoma cells, using XTT-based cell viability assays, western blotting, and liquid chromatography-mass spectrometry analysis. RESULTS: Verapamil and the MDM2-p53 antagonists potentiated vincristine-mediated growth inhibition in a concentration-dependent manner when used in combination with high MDR-1-expressing p53 mutant neuroblastoma cell lines at concentrations that did not affect the viability of cells when given alone. Liquid chromatography-mass spectrometry analyses showed that verapamil, Nutlin-3, MI-63 and NDD0005, but not RG7388, led to increased intracellular levels of vincristine in high MDR-1-expressing cell lines. CONCLUSIONS: These results show that in addition to Nutlin-3, other structurally unrelated MDM2-p53 antagonists can also act as MDR-1 inhibitors and reverse MDR-1-mediated multidrug resistance in neuroblastoma cell lines in a p53-independent manner. These findings are important for future clinical trial design with MDM2-p53 antagonists when used in combination with agents that are MDR-1 substrates.
Chiu B, Coburn J, Pilichowska M, et al. Surgery combined with controlled-release doxorubicin silk films as a treatment strategy in an orthotopic neuroblastoma mouse model. Br J Cancer. 2014; 111(4):708-15 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: Neuroblastoma tumour resection goal is maximal tumour removal. We hypothesise that combining surgery with sustained, local doxorubicin application can control tumour growth. METHODS: We injected human neuroblastoma cells into immunocompromised mouse adrenal gland. When KELLY cell-induced tumour volume was >300 mm(3), 80-90% of tumour was resected and treated as follows: instantaneous-release silk film with 100 μg doxorubicin (100IR), controlled-release film with 200 μg (200CR) over residual tumour bed; and 100 and 200 μg intravenous doxorubicin (100IV and 200IV). Tumour volume was measured and histology analysed. RESULTS: Orthotopic tumours formed with KELLY, SK-N-AS, IMR-32, SH-SY5Y cells. Tumours reached 1800±180 mm(3) after 28 days, 2200±290 mm(3) after 35 days, 1280±260 mm(3) after 63 days, and 1700±360 mm(3) after 84 days, respectively. At 3 days post KELLY tumour resection, tumour volumes were similar across all groups (P=0.6210). Tumour growth rate was similar in untreated vs control film, 100IV vs 100IR, and 100IV vs 200IV. There was significant difference in 100IR vs 200CR (P=0.0004) and 200IV vs 200CR (P=0.0003). Tumour growth with all doxorubicin groups was slower than that of control (P: <0.0001-0.0069). At the interface of the 200CR film and tumour, there was cellular necrosis, surrounded by apoptotic cells before reaching viable tumour cells. CONCLUSIONS: Combining surgical resection and sustained local doxorubicin treatment is effective in tumour control. Administering doxorubicin in a local, controlled manner is superior to giving an equivalent intravenous dose in tumour control.
Díaz-Carballo D, Acikelli AH, Bardenheuer W, et al. Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells. Int J Clin Pharmacol Ther. 2014; 52(9):787-801 [PubMed] Related Publications
Relapse of cancer months or years after an apparently successful therapy is probably caused by cancer stem cells (CSCs) due to their intrinsic features like dormant periods, radiorefraction, and acquired multidrug resistance (MDR) phenotypes, among other mechanisms of cellular drug evasiveness. Thus, the lack of currently efficacious interventions remains a major problem in the treatment of malignancies, together with the inability of existing drugs to destroy specifically CSCs. Neuroblastomas per se are highly chemotherapy-refractory extracranial tumors in infants with very low survival rates. So far, no effective cytostatics against this kind of tumors are clinically available. Therefore, we have put much effort into the development of agents to efficiently combat this malignancy. For this purpose, we tested several compounds isolated from Cuban propolis on induced CSCs (iCSC) derived from LAN-1 neuroblastoma cells which expressed several characteristics of tumor-initiating cells both in in-vitro and in-vivo models. Some small molecules such as flavonoids and polycyclic polyprenylated acylphloroglucinols (PPAP) were isolated using successive RT-HPLC cycles and identified employing mass spectrometry and NMR spectroscopic techniques. Their cytotoxicity was first screened in sensitive cell systems by MTT proliferation assays and afterwards studied in less sensitive neuroblastoma iCSC models. We found several compounds with considerable anti-iCSC activity, most of them belonging to the PPAP class. The majority of the compounds act in a pleiotropic manner on the molecular biology of tumors although their specific targets remain unclear. Nevertheless, two substances, one of them a flavonoid, induced a strong disruption of tubulin polymerization. In addition, an unknown compound strongly inhibited replicative enzymes like toposimerases I/II and DNA polymerase. Here, we report for the first time cytotoxic activities of small molecules isolated from Caribbean propolis which could be promising therapeutics or lead structures against therapy-refractory neuroblastoma entities. *Contributed equally.