Neuroblastoma is the most common extracranial solid tumor in infants and children. Our lab and others have shown trophic actions of gastrin-releasing peptide (GRP), and its analogue bombesin (BBS), in neuroblastomas. Our lab also found that undifferentiated neuroblastomas express increased levels of GRP receptor (GRPR). Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, a crucial regulator of cell survival, is associated with poor outcome in neuroblastomas and our lab¡¦s previous work has shown that GRPR regulates the expression of PI3K/Akt pathway components. However, the signaling mechanisms involved in this process are not clearly defined. Therefore, the objective of this project was to determine how GRP/GRPR, by way of PI3K pathway, regulates neuroblastoma growth. \r\n\r\nGRP/BBS treatment rapidly increased phosphorylation of both Akt and GSK-3ƒÒ in neuroblastoma cells. Antagonism or silencing of GRPR attenuated BBS-induced phosphorylation of Akt. PI3K inhibition also ...
Neuroblastoma is the most frequently diagnosed extracranial solid tumour in childhood. While a subset of tumours show spontaneous regression or complete remission following conventional treatment, a substantial number remain resistant to intensive multimodal therapies. Survival rates approaching 40% place high-risk neuroblastoma as one of the greatest challenges in paediatric oncology. This contemporary review provides an update on the diagnosis, risk stratification and management for this enigmatic tumour.. Neuroblastoma is the most common extracranial solid tumour in childhood and the most frequently diagnosed neoplasm during infancy.1 This malignant tumour consists of undifferentiated and/or differentiating cells originating from neural crest-derived sympathoadrenal precursors. Neuroblastoma is often described as "enigmatic" and "unpredictable" because of the broad spectrum of clinical behaviour ranging from life-threatening progression despite intensive treatment to complete spontaneous ...
TY - JOUR. T1 - Reversal of the effect of 12-O-tetradecanoyl-phorbol-13-acetate, TPA, on human neuroblastoma cells by nerve growth factor and mitomycin-C. AU - Goldstein, M. N.. AU - Malter, J. S.. PY - 1980. Y1 - 1980. UR - http://www.scopus.com/inward/record.url?scp=17544389097&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=17544389097&partnerID=8YFLogxK. M3 - Article. AN - SCOPUS:17544389097. VL - 87. JO - Journal of Cell Biology. JF - Journal of Cell Biology. SN - 0021-9525. IS - 2 II. ER - ...
TY - JOUR. T1 - Chromosomal aberrations and common fragile sites in neuroblastoma patients. AU - Vernole, P.. AU - Tedeschi, B.. AU - Pianca, C.. AU - Nicoletti, B.. AU - Riccardi, R.. AU - Melino, G.. PY - 1990. Y1 - 1990. N2 - We analyzed cytogenetically blood cells and bone marrow cells from 20 neuroblastoma patients. Chromosome common fragile sites were induced by aphidicolin in normal peripheral blood lymphocytes. All neuroblastoma patients showed a higher increase of aberrations after aphidicolin treatment as compared to that found in normal controls. In some cases it was possible to correlate the increase of the expression of a specific fragile site, 1p32, with deletions in the same area in bone marrow cells.. AB - We analyzed cytogenetically blood cells and bone marrow cells from 20 neuroblastoma patients. Chromosome common fragile sites were induced by aphidicolin in normal peripheral blood lymphocytes. All neuroblastoma patients showed a higher increase of aberrations after aphidicolin ...
Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P =.005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age ,/= 3 months at diagnosis was significant for EFS (P =. 043), it was less significant for survival (P =.077). The only other significant factor predictive for improved survival was favorable Shimada histopathologic classification. Sites of metastatic ...
Neuroblastoma is the most common extracranial solid tumor in childhood, with nearly 50% of patients presenting with widespread metastatic disease. The c
TY - JOUR. T1 - Regulation of tyrosine hydroxylase activity in mouse neuroblastoma clone N1E 115. AU - Richelson, E.. PY - 1973. Y1 - 1973. N2 - Mouse neuroblastoma (clone NIE 115) cells in the logarithmic growth phase were incubated for 12 days. From early log phase to late stationary phase, the specific activity of tyrosine hydroxylase (EC 1.14.3a) increased by more than 30 fold. The increase in tyrosine hydroxylase per cell and per dish was 12 and 2700 fold, respectively. When cell division was stopped by removing serum or by adding 0.1 mM 5 fluorodeoxyuridine and 0.1 mM uridine, the enzyme activity was also found to increase. These results show that tyrosine hydroxylase is regulated in neuroblastoma clone N1E 115.. AB - Mouse neuroblastoma (clone NIE 115) cells in the logarithmic growth phase were incubated for 12 days. From early log phase to late stationary phase, the specific activity of tyrosine hydroxylase (EC 1.14.3a) increased by more than 30 fold. The increase in tyrosine hydroxylase ...
TY - JOUR. T1 - Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation. AU - Zha, Yunhong. AU - Ding, Emily. AU - Yang, Liqun. AU - Mao, Ling. AU - Wang, Xiangwei. AU - McCarthy, Brian A.. AU - Huang, Shuang. AU - Ding, Hanfei. PY - 2012/8/7. Y1 - 2012/8/7. N2 - Retinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13) that are positioned sequentially from 3′ to 5′, with HOXD1 at the 3′ end and HOXD13 the 5′ end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2)-C cells, with the genes located at the 3′ end being activated generally earlier than those positioned more ...
eng] Stage 4S neuroblastoma (NB) is a special type of NB found in infants with metastases at diagnosis and is associated with an excellent outcome due to its remarkable capacity to undergo spontaneous regression. As genomics have not been able to explain this intriguing clinical presentation, we here aimed at profiling the DNA methylome of stage 4S NB to better understand this phenomenon. To this purpose, differential methylation analyses between International Neuroblastoma Staging System (INSS) stage 4S, stage 4 and stage 1/2 were performed, using methyl-CpG-binding domain (MBD) sequencing data of 14 stage 4S, 14 stage 4, and 13 stage 1/2 primary NB tumors (all MYCN non-amplified in order not to confound results). Stage 4S-specific hyper- and hypomethylated promoters were determined and further characterized for genomic localization and function by cytogenetic band enrichment, gene set enrichment, transcription factor target enrichment and differential RNA expression analyses. We show that ...
TY - JOUR. T1 - IGF-I receptor inhibition combined with rapamycin or temsirolimus inhibits neuroblastoma cell growth. AU - Coulter, Don W.. AU - Blatt, Julie. AU - DErcole, A. Joseph. AU - Moats-Staats, Billie M.. PY - 2008/5/1. Y1 - 2008/5/1. N2 - Background: Neuroblastoma is the third most common solid tumor in children. Treatment continues to be challenging. The pathogenesis of neuroblastoma has been related to expression of the type 1 insulin-like growth factor receptor (IGF1R) and to transcription factor MYC-N amplification. Previous studies have shown that MYC-N expression is disrupted by blockade of the IGF1R with a specific monoclonal antibody, αIR3. Inhibition of IGF1R signaling can be accomplished by other agents, including rapamycin or temsirolimus, which target mTOR (mammalian target of rapamycin). Materials and Methods: BE-2(c) and IMR-32 neuroblastoma cell lines were treated with varying concentrations of αIR3, rapamycin and temsirolimus alone or in combination and the viable ...
Abstract. Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, with about 700 new cases of neuroblastoma seen each year in the United States. The 5-year survival rate for children with high-risk NBL is only 50-60%, and this survival rate has not improved over the last 10 years. High-risk patients receive multimodality treatment, including chemotherapy, surgery, radiation therapy, biologic therapy and immunotherapy, all of which are associated with significant morbidity. Recent years have seen many advances in treatment of neuroblastoma, including therapeutic MIBG, immunotherapy, and personalized targeted therapy based on the genetic alterations seen in the tumor. The primary objective of this book is to provide the readers with a comprehensive review of neuroblastoma, from clinical aspects and the currently available treatment to recent advancements and future directions in the field of NBL treatment. The topics and chapters have been compiled keeping in mind a diverse ...
Neuroblastoma is the most common extracranial solid tumor of infancy. It is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells).
Melphalan could prolong the survival of children with advanced neuroblastoma and is currently used in many high-dose protocols for this patient group (20). The present study shows for the first time that J1, a prodrug of melphalan, is highly active against human neuroblastoma cell lines in vitro and in vivo. The cytotoxic activity of J1 in vitro was found to be superior compared with melphalan, and statistical comparisons also favored J1 in terms of antiproliferative, proapoptotic, and antiangiogenic activity in vivo. These findings are particularly interesting in view of the demonstrated clinical activity of Peptichemio in neuroblastoma (4, 5).. Despite different levels of absolute sensitivity, the seven human neuroblastoma cell lines displayed a similar pattern of sensitivity against the tested drugs (Pearson correlation of log IC50, 0.85-0.99), reflecting the importance of a common cytopathologic origin. The in vitro activity of J1 was, on average, 270-fold that of melphalan, with a range ...
VACCINE DOSING: Vaccine components SJNB-JF-IL2 and SJNB-JF-Lptn will each be dosed at 1x10e7 cells/m2. This will be given in conjunction with an escalating dose of SKNLP vaccine in the phase I portion of this study. In the phase II portion of this study, the same dose of SJNB-JF-IL2 and SJNB-JF-Lptn will be given in conjunction with the highest dose of SKNLP determined in the phase I portion. Vaccination will be administered on an inpatient or outpatient basis. Patient will be notified of which dose of vaccine cells they will receive if enrolled in the study.. Phase I Dose Escalation Component: While the investigators do not suspect that addition of a second irradiated, unmodified neuroblastoma tumor cell line to the previously tested SJNB-JF gene modified cell line will affect the safety profile of the vaccine, as the SKNLP has not been tested previously in vaccine studies, the investigators will perform an abbreviated dose escalation study of the combined vaccine to assess safety. The ...
TY - JOUR. T1 - Glucose metabolism in mixed glioblastoma and neuroblastoma cultures. AU - Newburgh, R. W.. AU - Rosenberg, Roger N.. PY - 1973/5/15. Y1 - 1973/5/15. N2 - When glioblastoma and neuroblastoma cells are mixed, an inhibition of 14CO2 evolution from [1-14C]-glucose occurs. This does not occur when Hela and Glioblastoma cells or Hela and neuroblastoma cells are mixed. Mixing the cells has no effect on the incorporation of [1-14C] glucose.. AB - When glioblastoma and neuroblastoma cells are mixed, an inhibition of 14CO2 evolution from [1-14C]-glucose occurs. This does not occur when Hela and Glioblastoma cells or Hela and neuroblastoma cells are mixed. Mixing the cells has no effect on the incorporation of [1-14C] glucose.. UR - http://www.scopus.com/inward/record.url?scp=0015789342&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=0015789342&partnerID=8YFLogxK. U2 - 10.1016/0006-291X(73)90757-2. DO - 10.1016/0006-291X(73)90757-2. M3 - Article. C2 - 4351142. AN - ...
In the present study, we provide evidence that freshly isolated neuroblastoma cells are susceptible to NK-mediated lysis. More importantly, we show that a key role in the lytic process is played by PVR, a molecule expressed at the tumor cell surface that is recognized by the DNAM-1 receptor. We analyzed highly purified, fresh neuroblastoma cells isolated from bone marrow aspirates (22) . As compared with cultured neuroblastoma cell lines (20) , freshly isolated neuroblasts were generally more resistant to lysis. Remarkably, a certain degree of variability existed among different tumors. In particular, we show that tumor cells displaying maximal susceptibility to lysis were characterized by high surface expression of PVR. This molecule was recently recognized as a ligand for DNAM-1, a surface receptor mediating NK cell activation and tumor cell killing (17) . In line with these findings, we now demonstrate that mAb-mediated disruption of DNAM-1-PVR interactions inhibits NK-mediated killing of ...
Rhabdomyosarcoma (RMS) is the third most common extracranial solid tumor of childhood. Approximately 350 new cases are diagnosed in the United States each year accounting for 3 percent of childhood cancers. RMS is derived from primitive myoblasts and morphologically resembles early stages of prenatal skeletal muscle differentiation. However, a large percentage of RMS tumors occur in locations normally lacking skeletal muscle, with the head and neck, genitourinary tract and retroperitoneum being frequent sites of tumor localization. Development of RMS has been associated with genetic tumor predisposition syndromes including Li-Fraumeni syndrome, neurofibromatosis and Costello syndrome. Childhood RMS is subdivided into two major subtypes, embryonal and alveolar, which have distinct histological features and genetic alterations. Adult RMS is largely a third histological subtype, namely pleomorphic RMS. The alveolar RMS subtype carries a poorer prognosis and is strongly myogenin positive by ...
Rhabdomyosarcoma (RMS) is the third most common extracranial solid tumor of childhood. Approximately 350 new cases are diagnosed in the United States each year accounting for 3 percent of childhood cancers. RMS is derived from primitive myoblasts and morphologically resembles early stages of prenatal skeletal muscle differentiation. However, a large percentage of RMS tumors occur in locations normally lacking skeletal muscle, with the head and neck, genitourinary tract and retroperitoneum being frequent sites of tumor localization. Development of RMS has been associated with genetic tumor predisposition syndromes including Li-Fraumeni syndrome, neurofibromatosis and Costello syndrome. Childhood RMS is subdivided into two major subtypes, embryonal and alveolar, which have distinct histological features and genetic alterations. Adult RMS is largely a third histological subtype, namely pleomorphic RMS. The alveolar RMS subtype carries a poorer prognosis and is strongly myogenin positive by ...
Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2- specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. Results: ...
Neuroblastoma is a childhood extracranial solid tumour that is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly requires characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and R1464STOP), which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression, we have employed cell culture-based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position 1174 (F1174I
Epidemiological and preclinical studies have revealed that omega-3 fatty acids have anticancer properties. We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) induces apoptosis of neuroblastoma cells in vitro by mechanisms involving intracellular peroxidation of DHA by means of 15-lipoxygenase or autoxidation. In our study, the effects of DHA supplementation on neuroblastoma tumor growth in vivo were investigated using two complementary approaches. For the purpose of prevention, DHA as a dietary supplement was fed to athymic rats before the rats were xenografted with human neuroblastoma cells. For therapeutic purposes, athymic rats with established neuroblastoma xenografts were given DHA daily by gavage and tumor growth was monitored. DHA levels in plasma and tumor tissue were analyzed by gas liquid chromatography. DHA delayed neuroblastoma xenograft development and inhibited the growth of established neuroblastoma xenografts in athymic rats. A revised version of the ...
OUTLINE: This is a multicenter study.. Previously collected samples are analyzed to define the genome-wide DNA copy number and allelic status; to define the genome-wide methylation profile of high-risk neuroblastoma cases; to define the genome-wide microRNA expression profile of high-risk neuroblastoma cases; to define the genome-wide RNA expression and relating gene expression to DNA copy number and gene polymorphisms, DNA methylation, and microRNA expression; to resequence three genomes: the neuroblastoma genome, the transcriptome, and the paired constitutional genome; and to characterize the relapsed high-risk neuroblastoma genome and epigenome.. PROJECTED ACCRUAL: A total of 300 tumor samples from patients with high-risk disease, 50 tumor samples from patients with low-risk primary neuroblastoma, and 30 human neuroblastoma-derived cell lines will be accrued for this study. ...
At the ASCO Plenary Session where the HR-NBL1/SIOPEN trial was presented, formal discussant Julie R. Park, MD, of the University of Washington, Seattle, said, "Large randomized trials have previously shown that myeloablative therapy improves outcomes in high-risk neuroblastoma, and it is now considered standard of care.". Dr. Park explained that the COJEC regimen used in this study may have contributed to the lower-than-expected 3-year event-free survival in the CEM arm. Previous studies conducted by the Childrens Oncology Group achieved a 3-year event-free survival of 46% with CEM, but those studies used a different induction regimen with lower doses of cisplatin and etoposide and did not include carboplatin.. "It is possible that rapid COJEC had a negative interaction with CEM, but not BuMel," she said.. "The SIOPEN trial is a great achievement and shows the unity of 20 European nations. This study confirms the importance of myeloablative therapy in a cohort of high-risk neuroblastoma with a ...
TY - JOUR. T1 - Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue. T2 - Results of the Chicago Pilot II study. AU - Kletzel, Morris. AU - Katzenstein, Howard M.. AU - Haut, Paul R.. AU - Yu, Alice L.. AU - Morgan, Elaine. AU - Reynolds, Marleta. AU - Geissler, Grant. AU - Marymount, Maryanne H.. AU - Liu, Dachao. AU - Kalapurakal, John A.. AU - Shore, Richard M.. AU - Bardo, Diana M.E.. AU - Schmoldt, Jennifer. AU - Rademaker, Alfred W.. AU - Cohn, Susan L.. PY - 2002/5/1. Y1 - 2002/5/1. N2 - Purpose: To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. Patients and Methods: From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II ...
Vella, S.; Conti, M.; Tasso, R.; Cancedda, R.; Pagano, A., 2012: Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells
Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein with four transmembrane-spanning domains that belongs to the PRAF protein family. Neuroblastoma (NB) is the most common malignant extracranial solid tumor of childhood that originates in primitive cells of the developing sympathetic nervous system. We investigated the correlation of PRAF2 mRNA expression to NB clinical and genetic parameters using Affymetrix expression analysis of a series of 88 NB tumors and examined the functional role of PRAF2 in an NB cell line using RNA interference. We found that high PRAF2 expression is significantly correlated to several unfavorable NB characteristics: MYCN amplification, high age at diagnosis, poor outcome and high INSS stage. The shRNA-mediated PRAF2 downregulation in the SK-N-SH NB cell line resulted in decreased cellular proliferation, migration and matrix-attachment. These findings were confirmed in NB patient tumor samples, where high PRAF2 expression is ...
Recently, we showed that high T-cell infiltration correlates with favorable clinical outcome in high-risk neuroblastoma patients (13). Herein, we demonstrate that TILs express PD-1 and LAG3, two negative regulators of T-cell function (33), and that neuroblastoma cells either express PD-L1 or HLA-I. According to the density of PD-L1+ and HLA-I+ tumor cells and regardless of infiltrating T-cell density, MYCN amplification status, INSS stage, and age at diagnosis, we could distinguish two PD-L1/HLA-I combinations: one associated with good prognosis (high HLA-I and low or no PD-L1) and the other associated with poor prognosis (low HLA-I and high or no PD-L1). Our findings provide a proof of principle that PD-L1 in combination with HLA-I expression may serve as a biomarker in neuroblastoma, although this has to be further confirmed by a prospective study with a larger number of samples.. Of note, a good PD-L1/HLA-I combination was also associated with favorable clinical outcome in intrahepatic ...
July 5, 2011 - A new treatment option may soon be available for children with neuroblastoma, according to research published in the July issue of The Journal of Nuclear Medicine. The study tested the principle that combined positron emission tomography and X-ray computed tomography (PET/CT) may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with a molecular radiotherapy known as 177Lu-DOTATATE. This therapeutic option was found to be a viable option for children with neuroblastomas. Neuroblastoma is a cancerous tumor that develops from nerve tissue in infants and children. Accounting for six to 10 percent of all childhood cancers, it does not always follow the same pattern, with some patients regressing spontaneously and other progressing, despite aggressive therapy. The long-term survival rate for neuroblastoma is below 40 percent. "We know that peptide receptor radionuclide therapy in adults with somatostatin-positive neuroendocrine tumors ...
TY - JOUR. T1 - Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma. T2 - A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study. AU - Di Giannatale, Angela. AU - Dias-Gastellier, Nathalie. AU - Devos, Annick. AU - Mc Hugh, Kieran. AU - Boubaker, Ariane. AU - Courbon, Frederic. AU - Verschuur, Arnaud. AU - Ducassoul, Stéphane. AU - Malekzadeh, Katty. AU - Casanova, Michela. AU - Amoroso, Loredana. AU - Chastagner, Pascal. AU - Zwaan, Christian M.. AU - Munzer, Caroline. AU - Aerts, Isabelle. AU - Landman-Parker, Judith. AU - Riccardi, Riccardo. AU - Le Deley, Marie Cecile. AU - Geoerger, Birgit. AU - Rubie, Hervé. PY - 2014/1. Y1 - 2014/1. N2 - Purpose To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma. Patients and Methods This multicenter, non-randomised, phase II study included children ...
The nature of the signal transducing the change in cell volume to the activation of osmolyte efflux pathways for RVD in osmotically swollen cells is not clear. Two major models have been proposed, one involving Ca2+ as an intracellular second messenger and the other in which RVD is mediated through Ca2+-independent mechanisms. According to the first model, cell swelling causes an increase in cytosolic Ca2+ that activates volume regulatory mechanisms. The increase in [Ca2+]i may result from Ca2+ influx, via plasma membrane channels (Christensen, 1987), or Ca2+ release from intracellular stores (McCarty and ONeil, 1992; Wu et al., 1997). The proposed effectors are mostly Ca2+-activated cation and anion channels and carriers. This model has been widely accepted as a paradigm for the involvement of Ca2+ as a transducing signal for RVD. Nevertheless, the existing evidence backing up this model is often weak and fragmentary, and the comprehensive analysis necessary to establish an active role of ...
TY - JOUR. T1 - Transplantation of a temperature-sensitive, nerve growth factor-secreting, neuroblastoma cell line into adult rats with fimbria-fornix lesions rescues cholinergic septal neurons. AU - Whittemore, S. R.. AU - Holets, V. R.. AU - Keane, Robert. AU - Levy, D. J.. AU - McKay, R. D G. PY - 1991/1/1. Y1 - 1991/1/1. N2 - The HT4 cell line was derived from infection of a mouse neuroblastoma cell line with a retrovirus that encoded the temperature-sensitive (ts) mutant of SV40 large T antigen. At nonpermissive temperature, HT4 cells differentiated with neuronal morphology, expressed neuronal antigens, synthesized nerve growth factor (NGF) mRNA, and secreted biologically active NGF in vitro. We sought to establish whether transplanted HT4 cells expressed class I major histocompatibility to complex (MHC) antigens, a partial requirement for recognition by cytotoxic T lymphocytes (CTL), and thus be susceptible to xenograft rejection. Differentiated HT4 cells expressed marginally detectable ...
Purpose: Neuroblastoma is the most common extracranial solid cancer type in childhood and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient anti-tumor immune responses. Therefore, we sought to enhance anti-tumor immunity by removing immunosuppression mediated by myeloid cells. Experimental Design: The prognostic values of myeloid cells are demonstrated by analyzing genomic datasets of neuroblastoma patients. The impact of tumor-derived factors on myelopoiesis and local induction of suppressive myeloid cells are dissected by in vitro culture models using freshly isolated human CD34+ hematopoietic stem cells, primary human monocytes and murine bone marrow cells. To test the therapeutic efficacy of BLZ945 as a monotherapy or in combination with checkpoint inhibitors, we employed a transgenic murine model (TH-MYCN) that develops aggressive spontaneous ...
Neuroblastomas are the most common extracranial solid childhood malignancies and the third commonest childhood tumors after leukemia and brain malignancies. The tumors typically occur in infants and very young children (mean age of presentation being ~22 months) with 95% of cases diagnosed before the age of 10 years.. Clinical presentation. Typically with pain or a palpable mass and abdominal distension, although numerous other presentations may be encountered due to local mass effect.. Location. Neuroblastomas arise from the sympathetic nervous system 2-3:. Intra-abdominal disease (two-thirds of cases) is more prevalent than the intrathoracic disease. Specific sites include:. ...
Ewing sarcoma is an aggressive bone tumor that occurs in children and young adults. Cure rates, particularly when disease has spread, are low with currently available treatments. Dr. Guenther aims to identify critical genes on which Ewing sarcoma cells are dependent for survival, with the goal of discovering weaknesses in these cancer cells that may be exploited to stop cancer growth. CITED2 is of particular interest as a Ewing sarcoma-specific dependency gene based on a genome-wide screen in hundreds of cancer cell lines. In some other cancers, CITED2 is described as important for helping cells repair damage and survive stress, such as when they are exposed to chemotherapy. She has found that CITED2 is present in higher levels in Ewing sarcoma cells than in other types of cancer, and when CITED2s function is turned off in Ewing sarcoma cells, they grow more slowly. She aims to first confirm that CITED2 is critical for Ewing sarcoma survival. She will also investigate what makes CITED2 ...
Hydroxybutyrate (GHB) is an endogenous metabolite synthesized in the brain. There is strong evidence to suggest that GHB has an important role as a neurotransmitter or neuromodulator.. The human aldo-keto reductase AKR7A2 has been proposed previously to catalyze the NADPH-dependent reduction of succinic semialdehyde (SSA) to GHB in human brain. In this study we have used RNA interference to evaluate the role of AKR7A2 in GHB biosynthesis in human neuroblastoma SH-SY5Y cells. Quantitative reverse transcription-PCR analysis and immunoblotting revealed that short interfering RNA molecules directed against AKR7A2 led to a significant reduction in both AKR7A2 transcript and protein levels 72 h post-transfection. We have shown that reduced expression of AKR7A2 results in a 90% decrease in SSA reductase activity of cell extracts. Furthermore, we have shown using gas chromatography-mass spectrometry that a decrease in the level of AKR7A2 was paralleled with a significant reduction in intracellular GHB ...
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Neuroblastoma is a cancerous tumor found in young children and infants, most commonly in children under age 5 and rarely in those older than 10. Approximately 650 children in the United States are diagnosed with neuroblastoma each year.. What causes neuroblastoma?. The cause of neuroblastoma is not certain, but researchers believe it forms from neuroblasts, immature nerve cells, that grow abnormally in the fetus due to a genetic mutation. In most neuroblastoma cases, scientists cannot identify the genetic abnormality or its cause.. Neuroblastoma often begins in the adrenal glands on top of the kidneys, but it also can begin in the chest, neck, or pelvis. In more than 70 percent of diagnosed cases, neuroblastoma tumors have metastasized, or spread, to other areas of the body such as the bones, bone marrow, lymph nodes, and liver.. ...
Histone methylation plays an important role in gene transcription and chromatin organization and is linked to the silencing of a number of critical tumor suppressor genes in tumorigenesis. G9a is a histone methyltransferase (HMTase) for histone H3 lysine 9. In this study, we investigated the role of G9a in neuroblastoma tumor growth together with the G9a inhibitor BIX01294. The exposure of neuroblastoma cells to BIX01294 resulted in the inhibition of cell growth and proliferation, and BIX01294 treatment resulted in the inhibition of the tumorigenicity of neuroblastoma cells in NOD/SCID mice. Therefore, G9a may be a potential therapeutic target in neuroblastoma. Moreover, we found several specific characteristics of autophagy after BIX01294 treatment, including the appearance of membranous vacuoles and microtubule-associated protein light chain 3 (LC3B). Similar results were observed in G9a-knockdown cells. In conclusion, our results demonstrated that G9a is a prognostic marker in neuroblastoma, and
Survival and distribution of transplanted human IMR-32 neuroblastoma cells. Article date: 1991/12/24 PubMed ID: 1814581 Journal name: Brain research (ISSN: 0006-8993) ABSTRACT The visualisation of transplanted cell lines is essential to determine both their viability and possible functional properties. Fluorescent latex microspheres were used to label cultured human neuroblastoma IMR-32 cells prior to transplantation. IMR-32 cells were first rendered amitotic by treatment with mitom…
Cancer therapy development has improved the survival rate of patients over the past few decades. The major limitation of this approach is the inevitable emergence of resistance upon patient relapse. Acquired drug resistance can develop over the course of treatment causing tumours to no longer respond to therapy. There are several mechanisms that have been proposed to contribute to this development. Platinum compounds, a major class of chemotherapy agents, are used in approximately half of all chemotherapy schedules. Cisplatin is an alkylating-like agent that causes DNA damage by binding to purine bases and forming DNA lesions, eventually leading to cell death. Regardless of cisplatins efficacy, there two major limitations for its use, severe cytotoxic side effects and the inevitable formation of drug resistance. For this project, two neuroblastoma cell lines UKF-NB-3 and UKF-NB-6, derived from late-stage high-risk neuroblastoma patients, have been adapted to cisplatin in order to investigate ...
Two Baylor College of Medicine physicians have received support from the nonprofit group Cookies for Kids Cancer for their research on neuroblastoma - a common type of solid tumor in children.. Dr. Leonid Metelitsa, associate professor of pediatrics at BCM and a pediatric oncologist at Texas Childrens Cancer Center, and Dr. Jed Nuchtern, professor of pediatrics and of surgery at BCM, who is a surgical oncologist at the center, each received $100,000 from the organization.. The funding supports their work to find new treatments for neuroblastoma. The survival rate for neuroblastoma is currently less than 40 percent, and it accounts for 15 percent of all pediatric cancer deaths.. Still difficult to treat. "The overall survival rate of childrens cancers has improved to about 80 percent today from 10 percent 30 years ago but the fact remains that some cancers, including some forms of neuroblastoma, are still very hard to treat," said Dr. David Poplack, director of Texas Childrens Cancer Center, ...
Green, R D. and Stanberry, L R., "Elevation of cyclic amp in c-1300 murine neuroblastoma by adenosine and related compounds and the antagonism of this response by methylxanthines." (1977). Subject Strain Bibliography 1977. 1535 ...
neuroblastoma - MedHelps neuroblastoma Center for Information, Symptoms, Resources, Treatments and Tools for neuroblastoma. Find neuroblastoma information, treatments for neuroblastoma and neuroblastoma symptoms.
phdthesis{d275ee82-4648-4ce3-902e-0e2d63580bc3, abstract = {The human neuroblastoma cell line SH-SY5Y can be induced to differentiate into a neuronal sympathetic phenotype after treatment with 16 nM 12-O-tetradecanoyl phorbol 13-acetate (TPA) in serum, or by a combination of the growth factors basic fibroblast growth factor and insulin-like growth factor-I (bFGF/IGF-I). SH-SY5Y cells stably transfected with TrkA, the nerve growth factor (NGF) receptor, differentiate in response to NGF. The function of protein kinase C (PKC) isoforms in these processes was investigated. SH-SY5Y cells were shown to express PKC-alpha, PKC-epsilon and PKC-zeta protein. All three isoforms remained present during TPA- and bFGF/IGF-I-induced differentiation, while a higher TPA concentration (1.6 µM), that does not promote differentiation, down-regulated PKC-alpha completely. The use of the PKC inhibitor GF 109203X demonstrated that TPA-induced differentiation is completely, while growth factor induced differentiation ...
Neuroblastoma is a highly malignant tumor of children that arises in the peripheral sympathetic nervous system, and spreads widely to bones and bone marrow. The survival of children with metastatic neuroblastoma is less than 40%, despite intensive chemotherapy, radiation and bone marrow transplant. Metaiodobenzylguanidine (MIBG) is a chemical similar in structure to noradrenaline and specifically taken up by neuroblastoma, thus providing a means to detect tumor metastases and to deliver intravenous tumor-targeted radiation by attaching a radioactive iodine molecule. 131I-MIBG has achieved responses of 40% in children with relapsed neuroblastoma, with very few side effects, but due to the special requirements of administering radioactive medicines, is used at only a few centers and is not yet approved for commercial use by the FDA. Furthermore, there is very little pre-clinical data on using MIBG in combination with the new molecularly targeted drugs to provide a platform for overcoming resistant ...
ABSTRACT: BACKGROUND: One of the most striking features of the childhood malignancy neuroblastoma (NB) is its clinical heterogeneity. Although there is a great need for better clinical and biological markers to distinguish between tumours with different severity and to improve treatment, no clear-cut prognostic factors have been found. Also, no major NB tumour suppressor genes have been identified. METHODS: In this study we performed expression analysis by quantitative real-time PCR (QPCR) on primary NB tumours divided into two groups, of favourable and unfavourable outcome respectively. Candidate genes were selected on basis of lower expression in unfavourable tumour types compared to favourables in our microarray expression analysis. Selected genes were studied in two steps: (1) using TaqMan Low Density Arrays (TLDA) targeting 89 genes on a set of 12 NB tumour samples, and (2) 12 genes were selected from the TLDA analysis for verification using individual TaqMan assays in a new set of 13 NB tumour
In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of
Cancer is driven, in part, by the interplay of regulatory transcription factors and dynamic alterations in chromatin structure. Previous studies of MYCN-amplified neuroblastoma have focused on the role of MYCN in transcriptional activation and the super-enhancer machinery to drive a neuroblastoma oncogenic program (20, 43, 56, 57). The role of MYCN in repressing tumor suppressor programs in neuroblastoma has not been as well explored. Our genome-scale CRISPR-Cas9 screen revealed a preferential dependency of neuroblastoma cells on the transcriptional silencing machinery of the PRC2 complex. Our mechanistic studies determined that MYCN directly drives the transcriptional repressor EZH2 in neuroblastoma, providing a direct link between MYCN overexpression and the repression of tumor suppressor programs in this disease. Specifically, EZH2 represses a neuronal differentiation program in MYCN-amplified neuroblastoma, enhancing the undifferentiated phenotype characteristic of neuroblastoma. Indeed, ...
Cancer is driven, in part, by the interplay of regulatory transcription factors and dynamic alterations in chromatin structure. Previous studies of MYCN-amplified neuroblastoma have focused on the role of MYCN in transcriptional activation and the super-enhancer machinery to drive a neuroblastoma oncogenic program (20, 43, 56, 57). The role of MYCN in repressing tumor suppressor programs in neuroblastoma has not been as well explored. Our genome-scale CRISPR-Cas9 screen revealed a preferential dependency of neuroblastoma cells on the transcriptional silencing machinery of the PRC2 complex. Our mechanistic studies determined that MYCN directly drives the transcriptional repressor EZH2 in neuroblastoma, providing a direct link between MYCN overexpression and the repression of tumor suppressor programs in this disease. Specifically, EZH2 represses a neuronal differentiation program in MYCN-amplified neuroblastoma, enhancing the undifferentiated phenotype characteristic of neuroblastoma. Indeed, ...
Although most neuroblastomas show a good response to initial chemotherapy, tumors from many patients with high-risk disease (stage IV diagnosed after 1 year of age and/or tumor with MYCN amplification) acquire drug resistance during the therapy (1 , 2) . Neuroblastomas established as cell lines and maintained without drug exposure in vitro manifest drug resistance that was acquired in patients and correlates with the intensity of chemotherapy employed in vivo, suggesting that selection occurs for tumor cells resistant to those drugs used during therapy (3 , 32) . Identification of the molecular events conferring drug resistance in neuroblastoma may allow developing therapies to overcome the particular form of drug resistance manifested by this tumor and could provide markers to identify patients likely to develop progressive disease when treated with currently available chemotherapeutic agents.. As p53 mutations are infrequent in primary neuroblastomas (18, 19, 20, 21, 22, 23) , it has been ...