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)

Eighteen hundred and eighty-four cases of human solid tumours and 833 samples of normal human tissues, formalin-fixed and paraffin-embedded, were examined immunohistochemically for expression of c-kit oncogene product using polyclonal antibody against synthesized c-kit peptide. Seminoma/dysgerminoma and small cell lung carcinoma (SCLC) show preferential c-kit expression at 92% and 36% frequency, respectively, whereas only sporadic cases of cervical carcinoma and non-SCLC lung carcinoma show c-kit positivity. A normal tissue counterpart positive for c-kit product is detected in the testis (spermatocyte) and ovary (oocyte) but not in the lung or the cervix. In contrast, normal epithelial cells of the breast, skin basal cells and tissue mast cells harbour c-kit product, but transformed cells of the former two are largely deficient in the c-kit protein. One hundred and thirty-nine neuroendocrine tumours and 39 non-pulmonary small cell carcinomas were all negative, except for two cases of neuroblastoma. This indicates a distinct character for SCLC in c-kit expression. The c-kit product may be a useful marker in diagnostic pathology of seminoma/dysgerminoma and SCLC among human solid tumours, and in distinction of SCLC from non-pulmonary small cell carcinoma.
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PMID:Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. 751 77

During development, mice with mutations of stem cell factor (SCF) or its receptor c-kit exhibit defects in melanogenesis, as well as hematopoiesis and gonadogenesis. Because melanocytes derive from neural crest cells, the role of SCF and c-kit was investigated in the neural crest-derived childhood tumor neuroblastoma. Using reverse transcription-polymerase chain reaction analysis, simultaneous expression of steady-state mRNA for the SCF ligand and its receptor c-kit was found in 14 of 14 (100%) human neuroblastoma cell lines and clones and in 8 of 18 (45%) human neuroblastoma tumor samples. Functional blockade of c-kit receptors in the cell lines SK-N-BE(2) and SH-SY5Y using the mouse monoclonal anti-c-kit antibody SR-1 resulted in a significant decrease in cellular growth rate when measured by either 3H-thymidine incorporation or clonogenicity. In addition, higher levels of c-kit mRNA expression were associated with parental neuroblastoma cell lines and subclones with a neuronal (N) differentiation phenotype, whereas lower levels of c-kit mRNA were associated with neuroblastoma cell line subclones having a schwannian/glial/melanocytic pattern of differentiation. However, the differentiation phenotype of neuroblastoma cell lines was not directly altered when c-kit expression was blocked using the SR-1 antibody. In summary, these data indicate that c-kit receptor expression may play a significant role in the growth regulation of the two neuroblastoma cell lines examined and suggest that c-kit may also play a similar role in neuroblastoma growth regulation in vivo. Simultaneous expression of SCF and c-kit mRNA in both neuroblastoma cell lines and tumors implies that c-kit may act as part of an autocrine growth loop in conjunction with endogenous production of SCF in this disease.
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PMID:Expression of stem cell factor and c-kit in human neuroblastoma. The Children's Cancer Group. 752 40

Stem cell factor (SCF) is a glycoprotein growth factor produced by marrow stromal cells that acts after binding to its specific surface receptor, which is the protein encoded by the protooncogene c-kit. SCF synergizes with specific lineage factors in promoting the proliferation of primitive hematopoietic progenitors, and has been administered to expand the pool of these progenitors in cancer patients treated with high-dose chemotherapy. SCF and its c-kit receptor are expressed by some tumor cells, including myeloid leukemia, breast carcinoma, small cell lung carcinoma, melanoma, gynecological tumors, and testicular germ cell tumors. Previous studies of SCF in neuroblastoma have produced conflicting conclusions. To explore the role of SCF in neuroblastoma, we studied five neuroblastoma lines (IMR-5, SK-N-SH, SK-N-BE, AF8, and SJ-N-KP) and the neuroepithelioma line CHP-100. All lines expressed mRNA for c-kit and c-kit protein at low intensity as measured by flow cytometry, and secreted SCF in medium culture as shown by ELISA. Exogenous SCF did not modify 3H thymidine uptake in the neuroblastoma and neuroepithelioma cell lines. After 6 days' culture in the presence of anti-c-kit, the number of viable neuroblastoma cells was significantly lower than the control, and terminal deoxynucleotidyl transferase assay showed a substantial increase of apoptotic cells: The percentage of positive cells was 1-3% in the control lines, whereas in the presence of anti c-kit it varied from 29% of SK-N-BE to 92% of CHP-100. After 9 days' culture in the presence of anti-c-kit, no viable cells were detectable. These data indicate that SCF is produced by some neuroblastoma cell lines via an autocrine loop to protect them from apoptosis.
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PMID:Stem cell factor suppresses apoptosis in neuroblastoma cell lines. 935 69

During development, mice with mutations of stem cell factor (SCF) or its receptor c-kit exhibit defects in melanogenesis, as well as hematopoiesis and gonadogenesis. Consequently, accumulating evidence suggests that the c-kit/SCF system plays a crucial role in all of these processes and in tumors which derive from them. Especially in neuroblastoma (infant tumors of neuroectoderm crest derivation such as melanocytes) it would appear that an autocrine loop exists between c-kit and SCF, and that the functional block of the c-kit receptors with monoclonal antibodies (MoAbs) results in a significant decrease in cellular proliferation. We studied the expression and role of c-kit and SCF in cell lines of soft tissue sarcoma of neuroectodermic origin, such as Ewing's sarcoma (ES) and peripheral neuro-ectodermal tumors (PNET). Using flow cytometry with MoAb CD117 PE, c-kit expression was highlighted in all six of the cell lines examined. This receptor was specifically and functionally activated by SCF, as shown by the binding experiments and the intracellular phosphotyrosine and immunoprecipitation studies that were performed. Using reverse transcriptase polymerase chain reaction analysis, five of the six cellular lines expressed the mRNA of SCF. In the medium measured by using an enzyme- linked immunosorbent assay, low concentrations of SCF were found: only the TC32 cellular line produced significantly higher levels (32 pg) than control. In serum-free culture the addition of SCF reduced the percentage of apoptotic cells from 25% to 90% in five out of the six cellular lines. This observation was confirmed by (1) the functional block of c-kit with MoAb: after 7 days of culture more than 30% of the cells were apoptotic (range 31.5% to 100%) in five out of six cell lines and there was also a decrease in the percentage of cells in phase S, and (2) c-kit antisense oligonucleotides: in the cellular lines treated with oligonucleotides (in relation to the untreated lines) there was a notable reduction (P < .001) both in the absolute number of cells and the 3H-thymidine uptake. These results indicate that ES and PNET express c-kit and its ligand SCF and that SCF is capable of protecting the tumor cells against apoptosis. Furthermore, the reverse transcriptase-polymerase chain reaction performed on the biopsies revealed the presence of mRNA both of SCF and c-kit in practically all of the samples studied. Our in vitro data lead us to assume that SCF may also inhibit tumor cell apoptosis in vivo.
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PMID:c-kit is expressed in soft tissue sarcoma of neuroectodermic origin and its ligand prevents apoptosis of neoplastic cells. 951 39

The expression of HIV-1 negative factor (nef) has been positively correlated with HIV disease progression [Z. Hanna, D.G. Kay, N. Rebai, A. Guimond, S. Jothy, P. Jocicoeur, Nef harbors a makor determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95 (1998) 163-175]. Nef expression has been detected in HIV infected human brains with neuronal damage [A. Ranki, M. Nyberg, V. Ovod, M. Haltia, I. Elovaara, R. Raininko, H. Haapsalo, K. Krohn, Abundant expression of HIV Nef and Rev proteins in brain astrocytes in associated with dementia, AIDS 9(9) (1995) 1001-1008; Y. Saito, L.R. Sharer, M.G. Epstein, J. Michaels, M. Mintz, M. Londer, K. Golding, B.M. Blumberg, Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmorten paediatric central tissues, Neurology 14 (1994) 474-480]. It is postulated that nef may contribute to the neuronal damage observed in the brain of those with late HIV disease. To test this, the potential toxicity of recombinant nef (from HIV-1 IIIB) was compared to the neurotoxin human tumour necrosis alpha (TNFalpha) on human brain cells in culture. SK-N-SH neuroblastoma, primary human neurons and glial cells were exposed to recombinant nef or TNFalpha protein for 3 days or twice over 6 days. Cell viability was assessed by Trypan Blue, lactate dehydrogenase (LDH) release and MTT assays. Nuclear fragmentation was detected using the Hoechst Blue nuclear dye assay. Both nef and TNFalpha (100 ng/ml) caused a significant 30% reduction of SK-N-SH cell numbers after 3 days exposure (P=0. 001). At this time, exposure to nef caused evident fragmented nuclei in these cultures. Human neuronal cultures had a 32 and 33% decrease in cell number after 6 days exposure to either nef or TNFalpha, respectively (P<0.001). Furthermore, as previously shown [J. He, C.M. DeCastro, G.R. Vandenbark, J. Busciglio, D. Gabuzda, Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protoonocogene, Proc. Natl. Acad. Sci. 94 (1997) 3954-3959], a 3-day exposure to nef significantly reduced human glial cell number by 25% (P=0.001). Recombinant nef and TNFalpha compromise human neurons in culture. Thus, like other virotoxins, it is shown for the first time that nef may also contribute to neuronal damage that has been reported in dementia in late HIV disease.
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PMID:Recombinant nef HIV-IIIB protein is toxic to human neurons in culture. 1080 40

The hemopoietin stem cell factor (SCF) and its receptor c-kit are expressed in some tumoral cells, including neuroblastoma (NB) cells. We have investigated the effect of retinoic acid (RA), one of the most active differentiating agents on human NB cells, on the SCF production by human neuroblastoma cell lines. SCF concentration was determined by immunoenzymatic assay in the supernatants of seven neuroblastoma cell lines. All cell lines except one showed detectable amounts of SCF in the supernatant in basal culture conditions. A progressive increase pattern of the SCF concentration over time, was common to all SCF secreting cell lines, both unstimulated and RA-stimulated. Moreover, after 48 and 72 hours-exposure to RA, SCF concentrations were higher than in the untreated controls (p < 0.01). Membrane SCF mRNA isoform was also detected by reverse-transcription polymerase chain reaction. These effects demonstrated that RA, besides inducing neuronal differentiation, enhanced SCF production in neuroblastoma cell lines.
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PMID:Retinoic acid modulates stem cell factor secretion by human neuroblastoma cell lines. 1120 72

Flt-3 ligand (FL) is a cytokine that promotes the survival, proliferation, and differentiation of hematopoietic progenitors in synergy with other growth factors, such as stem cell factor. Previously we have demonstrated that stem cell factor and its receptor c-kit are expressed in neural crest-derived tumor cells and that a c-kit block induces their apoptosis. Here we have evaluated the expression of flt-3 and its ligand in 12 neuroectodermal tumor cell lines from neuroblastoma (NB), neuroepithelioma (NE), Ewing sarcoma (ES), and peripheral neuroectodermal tumor (PNET) and in 38 biopsies: 19 from NB and 19 from ES and PNET. RT-PCR demonstrated the expression of flt-3 and FL in all lines. Coexpression was observed in 42% of NB and in 74% of ES and PNET biopsies. Flow cytometry confirmed the presence of membrane and cytoplasmic flt-3 and membrane FL in all lines, whereas soluble FL protein was not measurable in their supernatants. Microphysiometric demonstration of acidification of the medium provided evidence of the specific response of cell lines to FL stimulation. Specific flt-3 phosphorylation after FL treatment was also demonstrated by Western blotting analysis. In cells growing in RPMI plus 1% fetal calf serum, FL revealed a significant proliferating activity, more evident in NB and NE lines (mean increase of viable cells, 73 +/- 26% after 1 day). Treatment with flt-3 antisense oligonucleotides significantly inhibited cell growth. FL also displayed an antiapoptotic activity: after a 12-hour culture in the presence of 0.1% fetal calf serum, FL caused a 50% reduction of apoptotic cells. These results provide further evidence that neuroectodermal and hematopoietic cells share common regulatory pathways, and could be of interest in the clinical management of neuroectodermal tumors.
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PMID:Flt-3 and its ligand are expressed in neural crest-derived tumors and promote survival and proliferation of their cell lines. 1145 91

Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
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PMID:Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. 1201 61

Coexpression for c-Kit receptor and its ligand stem cell factor (SCF) has been described in neuroblastoma (NB) cell lines and tumors, suggesting the existence of an autocrine loop modulating tumor growth. We evaluated c-Kit and SCF expression by immunohistochemistry in a series of 75 primary newly diagnosed neuroblastic tumors. Immunostaining for c-Kit was found in 10/75 and for SCF in 17/75, with 5/10 c-Kit-positive tumors also expressing SCF. For both, c-Kit and SCF staining were predominantly found in the most aggressive subset of tumors, i.e., those amplified for MYCN: c-Kit was detected in 8/14 amplified vs. 2/61 single copy (p<0.001), and SCF in 9/14 amplified vs. 8/61 single copy tumors (p<0.001). Furthermore, the association of c-Kit expression with advanced stage (3 or 4) (p=0.001) and of SCF expression with adrenal primary (p=0.03) was substantiated. The in vitro activity of the tyrosine kinase inhibitor STI-571 (imatinib mesylate, Gleevec, Glivec) on NB cell lines positive or negative for c-Kit was also assessed. When cells were grown in 10% fetal calf serum, the 4 c-Kit-positive cell lines tested were sensitive to STI-571 growth inhibition to a different extent (ranging from 30 to 80%); also the c-Kit-negative cell line GI-CA-N was slightly affected, suggesting that other STI-571 targets operate in regulating NB proliferation. In addition, c-Kit-positive cell lines SK-N-BE2(c) and HTLA230, grown in SCF only, remained sensitive (40 and 70% of growth inhibition, respectively), while, in the same conditions, proliferation of the c-Kit-negative cell line GI-CA-N was not affected. Immunoprecipitation of c-Kit from cell lysates of SK-N-BE2(c) and HTLA230 cells grown in SCF and subsequent western blot analysis of the immunoprecipitates revealed a sharp decrease of c-Kit phosphorylation after STI-571 treatment. These data demonstrate that both c-Kit and SCF are preferentially expressed in vivo in the most aggressive neuroblastic tumors and that their signaling is active in promoting in vitro NB cell proliferation that can be selectively inhibited by treatment with STI-571.
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PMID:c-Kit is preferentially expressed in MYCN-amplified neuroblastoma and its effect on cell proliferation is inhibited in vitro by STI-571. 1280 Jan 87

Expression of the c-kit proto-oncogene product in neuroblastomas has been reported, but its clinical relevance is unclear. We determined the expression of c-kit by immunohistochemistry in a series of 155 neuroblastomas with long-term follow-up. The specificity of the reaction was verified by Western blot analysis and quantitative RT-PCR, and exon 11 of the kit gene was screened for mutations by PCR and capillary electrophoresis. No mutations were detected, and transcription of the kit gene correlated with protein expression. c-kit expression was associated with lower tumor stages and a low rate of MYCN amplification. More importantly, it coincided with tumor differentiation (P<0.0001), and portended a favorable outcome with a relative risk of 0.18 (P<0.0001). In a multivariate analysis of event-free survival, loss of c-kit (relative risk 4.25, P<0.0001) was an independent prognostic factor next to INSS stage 4 and before MYCN amplification. It is concluded that c-kit is transcriptionally regulated in neuroblastomas. Its expression likely identifies a subset of neuroblastomas with conserved capacity for differentiation, which may represent the embryonal variety of the disease. Assessment of c-kit may improve prognostic models for neuroblastoma and provide a basis for new therapy concepts.
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PMID:Expression of the c-kit receptor characterizes a subset of neuroblastomas with favorable prognosis. 1472 87


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