Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies, we demonstrated that human neuroblastoma cells are equipped with the machinery to direct their homing to bone marrow. These tumor cells express the CXCR4 receptor for the bone marrow stroma-derived chemokine CXCL12 (SDF-1) and secrete the CXCL12 ligand. The present study was undertaken to explore possible differences in gene-expression patterns between neuroblastoma variants that over-express CXCR4 (designated STH cells) and those which express very little of this receptor (STL cells). The results of the study clearly indicate that these variants show a differential gene-expression profile. They differ in expression of some integrins such as VLA2, VLA3 and VLA6, of neuroendocrine-markers such as CD56 and synaptophysin, in the expression of c-kit and in the secretion of certain cytokines and growth factors such as TNFalpha, SDF-1, VEGF, IL-8, GM-CSF and IP-10. We hypothesize that these differences are due to an autocrine SDF-1alpha-CXCR4 axis.
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PMID:The tumor microenvironment: CXCR4 is associated with distinct protein expression patterns in neuroblastoma cells. 1508 41

A therapeutic role of STI571 (imatinib mesylate) has been anticipated in patients with c-Kit positive neuroectodermal tumors. We examined the efficacy of STI571 to inhibit expansion of c-Kit positive neuroectodermal tumor cell lines in vitro and in a mouse model inoculated with ES (Ewing sarcoma) derived tumor cells, and investigated the molecular mechanism of STI571 action. Eleven tumor lines of ES, PNET (primitive neuroectodermal tumors) and NB (neuroblastoma) were assayed in the presence of 1, 5, 10, 15, 20 or 30 micro M STI571 for 24, 48, 72 h and 7 days. The mechanism of STI571 action was investigated using a microphysiometer cytosensor that determines cellular metabolic rates in the presence of STI571. c-Kit and global protein phosphorylation was assayed by immunoprecipitation and a direct enzyme-linked immunoadsorbent assay after 72 h of 10 micro M STI571. Apoptosis was investigated by propidium iodide (PI), Annexin V staining and by enzymatic activity of caspase-3. Moreover, apoptotic gene expression was investigated using microarray technology. In nude mice, tumor volume and histology were analyzed in STI571 treated and untreated mice, and apoptotic gene expression analysis was performed on tumor masses. A decrease in cell proliferation and increase of cell apoptosis was caused by STI571 in a concentration- and time-dependent manner. Cytosensor microphysiometer and immunoprecipitation experiments demonstrated a time- and concentration-dependent decrease of cellular metabolic activity and global protein dephosphorylation after STI571 exposure. The inhibition by STI571 appeared at least to some extent independent of c-Kit inhibition since cells remained sensitive to SCF stimulation. Tumor volume was significantly reduced in STI571-treated mice compared to tumors from control inoculated non-treated mice. The apoptosis pathway in response to STI571 appeared not to be dependent on caspase activation, while gene expression profiles suggested accumulation of reactive oxygen species (ROS) resulting in cell death after exposure to STI571. The results point to the potential relevance of STI157 for neuroectodermal tumor therapy in view of its inhibitory effect on tumor cell growth, in spite of the observation that the inhibition of the c-Kit signaling pathway is not critically involved.
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PMID:Imatinib mesylate (STI571) interference with growth of neuroectodermal tumour cell lines does not critically involve c-Kit inhibition. 1528 88

We have prepared the map of regional distribution of cervical cancer in Hungary. Serial HPV genotyping of sexual partners provided evidence for the sexually transmitted infections. Molecular epidemiology studies revealed activating c-kit mutation in bilateral testicular cancers. A cost-effective molecular staging method was introduced to the management of breast cancer patients. Genomic profiling identified the gene signature of Herceptin and taxane sensitivity of breast cancer. In colon cancer patients we have determined the mutational spectrum of hMLH1 and hMSH2 genes in Hungary. The prognostic power of SHMT and MTHFR polymorphism was determined in colorectal cancer patients. In head and neck cancer the gene signature of cisplatin sensitivity and the EGFR polymorphism was determined. We have introduced a cost-effective in vitro assay to determine the drug resistance of pediatric leukemias. The prognostic power of N-myc genotyping was determined in neuroblastoma patients. A phase I trial for gene therapy of brain cancer was started by using a GM-CSF adenoviral vector system. Using global genomic approaches the gene signature of malignant melanoma and its metastatic disease was determined. We have found that Ca-channel blockers and EGFR tyrosine kinase inhibitors are effective in preclinical human melanoma models in breaking the apoptosis resistance of this tumor.
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PMID:[Activity of the National Oncology R&D Consortium in 2004]. 1590 26

Fanconi's anemia (FA) is an autosomal recessive inherited syndrome with a predisposition to malignancy. The association between FA and solid pediatric tumors is extremely rare. The authors report a rare case of VACTERL syndrome associated with FA and multiple solid pediatric tumors occurring in a very young girl. This child had numerous congenital anomalies (horseshoe kidney, cerebella hypoplasia, microcephaly, sacral agenesis) and esophageal atresia, which was repaired in neonatal period. Such association led quickly to the diagnosis of FA. At age of 11 months, she developed simultaneously a renal tumor in a horseshoe kidney and bilateral adrenal tumors. The left adrenal mass was removed, and partial nephrectomy was performed. Histological analysis concluded to adrenal neuroblastoma and nephroblastoma. We also evaluated the c-kit expression in these tumors to propose a therapeutic alternative to chemotherapy by oral agent STI-571 (Gleevec; Novartis, East Hanover, NJ). Strong cytoplasmic immunostaining of c-kit was found in both tumors. Unfortunately, she quickly developed a posterior cerebellar fossa tumor and died 1 month later. This clinical situation is very rare but suggests that young patients with FA and solid pediatric tumors may belong to a particular subgroup of FA. Further studies are necessary to test if STI-571 treatment could be efficient in such patients with pediatric tumors.
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PMID:Bilateral adrenal neuroblastoma and nephroblastoma occurring synchronously in a child with Fanconi's anemia and VACTERL syndrome. 1641 81

Neuroblastoma (NB) expresses the tyrosine kinase receptors c-Kit, PDGFR-alpha and -beta-targets for STI-571. We investigated a possible combination therapy of STI-571 with retinoic acid (RA) and gamma-irradiation on NB cell viability in vitro. Expression of tyrosine kinase receptors and their ligands was examined in 6 NB cell lines by RT-PCR and FACS. The effect on cell viability was determined by MTT assay. Cell viability of all 6 NB cell lines was significantly inhibited after treatment with 20 microM STI-571 for 72h, two cell lines responding already to 10 microM. Cell lines responded irrespective of their mRNA status or cell surface expression of c-Kit, PDGFR-alpha and -beta. Co-incubation with 9-cis RA sensitized cells to the inhibitory effects of STI-571. However, pre-treatment with 9-cis RA resulted in resistance of NB cell lines to STI-571 and gamma-irradiation. Treatment of NB with STI-571 in combination with 9-cis RA might be a therapeutic strategy for patients in consolidation therapy who have completed gamma-irradiation therapy.
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PMID:Effect of STI-571 (imatinib mesylate) in combination with retinoic acid and gamma-irradiation on viability of neuroblastoma cells. 1652 60

We worked out an experimental protocol able to purge the stem cell compartment of the SH-SY5Y neuroblastoma clone. This protocol was based on the prolonged treatment of the wild-type cell population with either hypoxia or the antiblastic etoposide. Cell fate was monitored by immunocytochemical and electrophysiologic (patch-clamp) techniques. Both treatments produced the progressive disappearance of neuronal type (N) cells (which constitute the bulk of the tumor), leaving space for a special category of epithelial-like substrate-adherent cells (S(0)). The latter represent a minimal cell component of the untreated population and are endowed with immunocytochemical markers (p75, c-kit, and CD133) and the electrophysiologic "nude" profile, typical of the neural crest stem cells. S(0) cells displayed a highly clonogenic potency and a substantial plasticity, generating both the N component and an alternative subpopulation terminally committed to the fibromuscular lineage. Unlike the N component, this lineage was highly insensitive to the apoptotic activity of hypoxia and etoposide and developed only when the neuronal option was abolished. Under these conditions, the fibromuscular progeny of S(0) expanded and progressed up to the exhaustion of the staminal compartment and to the extinction of the tumor. When combined, hypoxia and etoposide cooperated in abolishing the N cell generation and promoting the conversion of the tumor described. This synergy might mirror a natural condition in the ischemic areas occurring in cancer. These results have relevant implications for the understanding of the documented tendency of neuroblastomas to regress from a malignant to a benign phenotype, either spontaneously or on antiblastic treatment.
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PMID:Purging of the neuroblastoma stem cell compartment and tumor regression on exposure to hypoxia or cytotoxic treatment. 1736 56

Neuroblastoma (NB) is the most common malignant solid tumor in childhood. There are well-recognized prognostic factors in NB such as age at diagnosis, organ of origin, stages, MYCN gene amplification, and expression of H-ras, trkA and survivin. Moreover, we investigated the expression of vascular endothelial growth factor (VEGF), tyrosine hydroxylase (TH), p53, stem cell factor (SCF) and c-kit of its receptor with quantitative real-time polymerase chain reaction (PCR) in 22 NBs and 4 other tumors (one malignant lymphoma, one malignant teratoma, and 2 rhabdomyosarcomas) samples. The correlation between patients' prognoses and the expression of TH or c-kit was newly recognized, particularly the good prognosis in patients in whom c-kit highly expressed and the poor prognosis contrarily associated with low or no expression, although the SCF of its ligand had no relationship with patient prognosis. It is possible that tumors without c-kit expression can not react with SCF (via the autocrine or paracrine system) and remain immature. It may be that this is a new critical clinical event in NB patients.
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PMID:Analyses of novel prognostic factors in neuroblastoma patients. 1805 15

High HIF-2alpha protein levels in the sympathetic nervous system-derived childhood tumour neuroblastoma as well as immature phenotype correlate to unfavourable outcome. Here we show that a small subset of perivascularly located, strongly HIF-2alpha-positive tumour cells (MYCN amplified) lacks expression of differentiation markers, but expresses neural crest and early sympathetic progenitor marker genes such as Notch-1, HES-1, c-Kit, dHAND, and vimentin. HIF-2alpha- and CD68-positive tumour-associated macrophages were frequently found close to the immature and HIF-2alpha-positive neuroblastoma cells and as VEGF levels are high in the perivascular niche, we hypothesize that neuroblastoma neural crest-like cells and macrophages cooperate to facilitate angiogenesis and thereby contribute to the aggressive neuroblastoma phenotype.
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PMID:High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. 1818 31

It is a general opinion that tissue-specific stem cells are present in adult tissues but their specific properties remain elusive. They are rare in tissues and heterogeneous; in addition, their identification and the characterization of their progeny has encountered technical difficulties. In particular, the existence of pancreatic stem cells remains elusive because specific markers for their identification are not available. We established a method for the isolation of a population of stem/progenitor cells from the human exocrine pancreas, and propose it as a model for other human compact organs. We also used markers that identified and finally characterized these cells. Spheroids with self-replicative potential were obtained from all specimens. The isolated population contained a subset of CD34+ CD45- cells and was able to generate, in appropriate conditions, colonies that produce insulin. We obtained evidence that most freshly isolated spheroids, when co-cultured with the c-kit positive neuroblastoma cell line LAN 5, produced a c-kit positive progeny of cells larger in their cytoplasmic content than the original spheroid population, with elongated morphology resembling the neuronal phenotype. We identified a novel predominant functional type of stem/progenitor cell within the human exocrine pancreas, able to generate insulin-producing cells and potentially non-pancreatic cells.
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PMID:Identification and characterization of a novel expandable adult stem/progenitor cell population in the human exocrine pancreas. 1859 92

Imatinib is currently in early clinical trials as targeted therapy for relapsed neuroblastomas and other childhood solid tumors expressing platelet-derived growth factor receptors (PDGFR) or c-Kit. Short-term treatment with imatinib in clinically achievable concentrations is ineffective in neuroblastoma in vitro. However, clinically, imatinib is administered daily over long time periods. The effects of combining imatinib with chemotherapy in neuroblastoma are unknown. Here, a panel of neuroblastoma cell lines (n = 5) were studied, representing tumors with different biological (MYCN-amplification +/-) and clinical (drug resistance) features. Using a protracted low-dose treatment schedule (1-3 weeks; 0.5-5microM) imatinib dose-dependently inhibited proliferation and clonogenic survival for all tested cell lines with IC50 <2.5microM. In contrast, short-term treatment (<96 hrs) was ineffective. Low-dose imatinib was synergistic in combination with doxorubicin and caused increased G2/M- and S-phase arrest and apoptosis as evidenced by enhanced caspase-3 activation and sub-G1 DNA accumulation. A significant but less pronounced effect was observed when imatinib was combined with etoposide or vincristine, as opposed to cisplatin, melphalan, or irinotecan. All cell lines expressed PDGFRbeta, whereas no protein expression of PDGFRalpha was detected in MYCN amplified cell lines. PDGF-BB caused PDGFRbeta phosphorylation and partially rescued neuroblastoma cells from doxorubicin-induced apoptosis, in an imatinib-sensitive manner. In vivo, treatment with imatinib in combination with doxorubicin induced a significant growth inhibition of established neuroblastoma xenografts. These findings suggest clinical testing of imatinib in combination with selected chemotherapeutic drugs, in particular doxorubicin, in children with high-risk neuroblastoma.
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PMID:Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo. 1905 99


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