Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of haem oxygenase-1 (HO-1) as well as nitric oxide (NO) biosynthesis during tumour growth was investigated in an experimental solid tumour model (AH136B hepatoma) in rats. An immunohistochemical study showed that the inducible isoform of NO synthase (iNOS) was localized in monocyte-derived macrophages, which infiltrated interstitial spaces of solid tumour, but not in the tumour cells. Excessive production of NO in the tumour tissue was unequivocally verified by electron spin resonance spectroscopy. Tumour growth was moderately suppressed by treatment with either Nomega-nitro-L-arginine methyl ester (L-NAME) or S-methylisothiourea sulphate (SMT). In contrast, HO-1 was found only in tumour cells, not in macrophages, by in situ hybridization for HO-1 mRNA. HO-1 expression in AH136B cells in culture was strongly enhanced by an NO (NO+) donor S-nitroso-N-acetyl penicillamine. HO-1 mRNA expression in the solid tumour in vivo decreased significantly after treatment with low doses of NOS inhibitors such as L-NAME and SMT (6-20 mg kg(-1)). However, the level of HO-1 mRNA in the solid tumour treated with higher doses of NOS inhibitor was similar to that of the solid tumour without NOS inhibitor treatment. Strong induction of HO-1 was also observed in solid tumours after occlusion or embolization of the tumour-feeding artery, indicating that ischaemic stress which may involve oxidative stress triggers HO-1 induction in the solid tumour. Lastly, it is of great importance that an HO inhibitor, zinc protoporphyrin IX injected intra-arterially to the solid tumour suppressed the tumour growth to a great extent. In conclusion, HO-1 expression in the solid tumour may confer resistance of tumour cells to hypoxic stress as well as to NO-mediated cytotoxicity.
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PMID:Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. 1047 Oct 43

Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS+ epithelial cells or total epithelial cells was 69+/-16% (n = 50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62+/-20% (n = 40), compared to 12+/-9% (n = 40) in samples of grade III carcinomas (P<0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n = 4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumor's metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.
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PMID:Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade. 1057 7

The relationship between nitric oxide (NO) synthase II (NOS II) expression and the metastatic ability of tumor cells is inconclusive. We determined the role of host NOS II expression in the growth and metastasis of the B16-BL6 murine melanoma and M5076 murine ovarian sarcoma cell lines. The cells were either s.c. or i.v. injected into syngeneic wild-type (NOS H+/+) and NOS II-null (NOS H-/-) C57BL/6 mice. Both cell lines produced slightly larger s.c. tumors in NOS H-/- mice than in NOS II+/+ mice. However, B16- BL6 cells produced more and larger experimental lung metastases in NOS II+/+ mice than in NOS II-/- mice, whereas M5076 cells produced fewer and smaller experimental lung metastases in NOS II+/+ mice than in NOS II-/- mice. After activation with IFN-gamma and lipopolysaccharide, macrophages isolated from NOS II+/+ C57BL/6 mice produced NO-dependent cytotoxicity in sarcoma cells, whereas macrophages from NOS II-/- C57BL/6 mice did not. In contrast, activated macrophages produced little to no NO-mediated cytotoxicity in melanoma cells. Immunostaining analyses indicated that NOS II expression was apparent in the metastases growing in NOS H+/+ mice and correlated with increased cell proliferation in B16-BL6 lung metastases but with decreased cell proliferation in M5076 liver metastases. Our data suggest that disruption of host NOS II expression enhanced the growth and metastasis of NO-sensitive tumor cells but suppressed the metastasis of NO-resistant tumor cells, proposing that host-derived NO may differentially modulate tumor progression.
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PMID:Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis. 1082 24

Nitric oxide (NO) can play an important role in the regulation of vascular tone and neurotransmission, as well as in non-specific immunoreactions and inflammation in a variety of tissues. Increased quantities of nitric oxide in respired air can be measured during inflammatory processes. However, the exact role and precise sources of NO under physiological and pathophysiological conditions within the airways remain to be defined. Three isoforms of NO-synthases can be distinguished: two constitutive (neuronal and endothelial) Ca(2+)-dependent cNOS and one inducible Ca(2+)-independent iNOS (NOS II). Constitutive NOS (NOS I and III) release a basal amount of NO under physiological conditions. The inducible form once expressed can catalyse the generation of large quantities of NO. Many kinds of cells, such as macrophages, neutrophils, endothelium and smooth muscle cells, are capable of expressing NOS II. Since all isoforms of NO-synthase seem to be present in nasal tissues and the expression of iNOS under inflammatory conditions seems to be responsible for excessive production of NO, the distribution of NOS-isoforms (especially NOS II) in normal and inflammatory nasal tissue, as well as the exact requirements for expression of iNOS remain to be proven. Non-inflamed fresh human nasal mucosa from the middle turbinate was compared immuno-histologically with nasal mucosa having the typical findings of chronic polypoid rhinosinusitis (i.e., polypoid middle turbinates and polyps of the middle nasal duct). In order to gain more information about the mechanisms of acute inflammation, non-inflamed vital turbinates were incubated in vitro with the proinflammatory substances bacterial lipopolysaccharides (LPS) and tumor necrosis-factor (TNF) for 30, 60, 90, 120, 180 and 240 min. Subsequent to exposure to NADPH-diaphorase and immunostaining with specific antibodies to each NOS-isoform, clearly increased or initiated expressions of inducible NOS (iNOS) in blood vessels, glands, macrophages and epithelium of chronically inflamed and LPS-incubated nasal tissue became apparent in comparison to the non-inflamed controls. In contrast, NOS III/NOS I seemed to be not affected. The onset of immunohistochemically recognizable NOS II expression was observed after 90 min incubation with of LPS/TNF-alpha. Polypoid tissue showed a strong increase in submucosal thickness and a high infiltration of iNOS-positive leukocytes (granulocytes and macrophages) compared to the LPS-incubated non-inflamed specimens. These findings implicate NOS II generated nitric oxide as a key agent for causing swelling, secretion and obstruction in patients with acute and chronic polypoid or allergic rhinitis. These findings also suggest that molecular NO has to be considered in the pathophysiology of chronic polypoid rhinosinusitis.
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PMID:[Detection of nitric oxide synthases in physiological and pathophysiological processes of the nasal mucosa]. 1095 25

To investigate whether expression of E-cadherin correlates with polarised tissue organisation, grade or tumour type in salivary neoplasms, frozen sections from 30 salivary gland neoplasms were stained immunohistochemically for E-cadherin using the antibody HECD-1 and compared to the staining patterns in five samples of normal salivary gland. Lesions with areas of lack of staining were restained at two higher antibody concentrations. Normal salivary gland stained strongly around the periphery of acinar and ductal cells. Neoplasms mostly stained strongly regardless of neoplasm type. Reproducible loss of expression was found only in epithelial cells showing stromal or plasmacytoid (hyaline) differentiation in pleomorphic adenoma. Low- and high- grade mucoepidermoid carcinomas, adenocarcinoma NOS and carcinoma ex pleomorphic adenoma showed focal loss of expression but this was not related to tissue architecture, differentiation or invasiveness. We conclude that the relationship seen between E-cadherin expression and cell polarity/glandular organisation in breast and colon does not appear to exist for salivary gland neoplasms in which the diversity of architectural patterns precludes detection of any simple relationship. E-cadherin expression seems unlikely to be a useful marker for diagnosis or prognosis in salivary neoplasia in general.
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PMID:Expression of E-cadherin, cellular differentiation and polarity in epithelial salivary neoplasms. 1103 44

Nitric oxide synthase inhibitors block the neoplastic transformation of C3H 10T1/2 cells in vitro. Evidence presented herein suggests that they mediate their effects early in the carcinogenic process as brief treatment with the NOS inhibitor aminoguanidine (AG) during log phase cell growth (initiation phase) is sufficient to block foci formation. In contrast, treatment initiated after formation of a confluent monolayer was associated with diminished protection, while treatment commencing late in the promotional phase had no protective effect and appeared to enhance the number and stage of foci observed. These findings suggest that while AG treatment can inhibit transformation during the early promotional phase, it most effectively inhibits transformation during the initiation phase. In general AG enhanced growth of both normal and tumor cells, suggesting that effects on growth were unrelated to its anti-transformation properties, however, these effects could be related to the effect on tumor cell stage noted above. Although induction of inducible nitric oxide synthase (iNOS) by treatment with LI during the last 2 weeks of the assay was associated with enhanced transformation, the efficacy of AG in protecting against transformation was not clearly associated with substantial reductions in NO synthesis. The data suggest that AG inhibits transformation early in the transformation process independently of iNOS inhibition and that AG may have deleterious effects late in the process, possibly through stimulation of tumor cell growth.
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PMID:The role of nitric oxide in neoplastic transformation of C3H 10T1/2 embryonic fibroblasts. 1106 59

Tumor necrosis factor alpha (TNF-alpha) exerts its effect by two distinct signaling pathways. It can trigger cytotoxicity in sensitive target cells. TNF-alpha can also promote nuclear factor kappaB (NF-kappaB) activity and regulate the expression of genes that interfere with apoptosis and thus conferring resistance to several apoptotic stimuli. We have observed that interferon-gamma (IFN-gamma) sensitizes human ovarian carcinoma cell lines to TNF-alpha-mediated apoptosis and further, IFN-gamma induces the expression of the inducible nitric-oxide synthase (iNOS) and the generation of nitric oxide (NO). This study examines the role of NO in the sensitization of the ovarian carcinoma cell line AD10 to TNF-alpha-mediated cytotoxicity. Treatment of AD10 cells with the NOS inhibitor l-NMA blocked the IFN-gamma-dependent sensitization whereas NO donors (S-nitroso-N-acetylpenicillamine) sensitized these cells to TNF-alpha cytotoxicity. Analysis of the activation status of NF-kappaB upon treatment with NO donors confirmed the inhibitory role of NO on both the NF-kappaB DNA-binding property and its activation. Moreover, the inhibition of NF-kappaB nuclear translocation by NO donors directly correlated with the intracellular concentration of H(2)O(2) and was reversed by the addition of exogenous H(2)O(2). These findings show that NO might interfere with TNF-alpha-dependent NF-kappaB activation by interacting with O(2) and reducing the generation of H(2)O(2), a potent NF-kappaB activator. Therefore, NO-mediated disruption of NF-kappaB activation results in the removal of anti-apoptotic/resistance signals and sensitizes tumor cells to cytotoxic cytokines like TNF-alpha.
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PMID:Nitric oxide disrupts H2O2-dependent activation of nuclear factor kappa B. Role in sensitization of human tumor cells to tumor necrosis factor-alpha -induced cytotoxicity. 1111 42

Previous studies have shown that enforced expression of IFN-beta suppressed tumor growth and metastasis. In this report, we determined whether the induction of nitric oxide synthase II (NOS II) gene is required for IFN-beta-mediated antitumor activity using syngeneic mice with intact (NOS II+/+) or genetically disrupted (NOS II-/-) NOS II gene. PANC02-H7 highly metastatic murine pancreatic adenocarcinoma cells were transfected with an IFN-beta expression vector or a control pcDNA3 vector. The parental PANC02-H7, control vector-transfected, and IFN-beta-transfected cells were orthotopically implanted into the pancreas of syngeneic NOS II+/+ and NOS II-/- C57BL/6J mice. In NOS II+/+ C57BL/ 6J, both parental and control vector-transfected cells grew progressively in pancreas and produced numerous liver metastases and a large amount of malignant ascites, whereas IFN-beta-secreting cells did not. In NOS II-/- C57BL/6J mice, however, IFN-beta-secreting cells grew much more aggressively. Higher NO induction was detected in NOS II+/+ mice that received injections with IFN-beta-secreting cells than with the control cells, but it was not detected in NOS II-/- mice. These data suggested that IFN-beta secreted from tumor cells stimulates NO production by host cells and suppresses tumor growth and metastasis.
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PMID:Intact nitric oxide synthase II gene is required for interferon-beta-mediated suppression of growth and metastasis of pancreatic adenocarcinoma. 1119

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.
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PMID:Nitric oxide and angiogenesis. 1124 73

Expression of iNOS in glioma and other tumors has been extensively documented but the effects of NO derived from iNOS on tumor-killing mechanisms of chemotherapy drugs remain to be fully defined. We note that increased NO synthesis by cytokine exposure or iNOS overexpression neutralized the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but not cisplatin, in rat C6 glioma cells. Suppression of BCNU cytotoxicity associated with iNOS overexpression could be abolished by pharmacological inhibition of NOS or coexpression of an antisense RNA against iNOS. Both BCNU and CCNU are chloroethylnitrosoureas that kill tumor cells via carbamoylating and alkylating actions. Further studies using compounds that each carry these different activities indicate that iNOS neutralized carbamoylating, but not alkylating, action of chloroethylnitrosoureas. Temozolomide, a novel chemotherapy drug recently available for treating brain tumors, carries only alkylating, but not carbamoylating, action. Overexpression of iNOS in C6 cells failed to neutralize temozolomide cytotoxicity. Results from the present study demonstrate the ability of iNOS-derived NO to confer chemoresistance against the carbamoylating potential of chloroethylnitrosoureas in vitro. Further investigation is needed to test whether iNOS expression, frequently noted in malignant brain tumors, also enhances chemoresistance against chloroethylnitrosoureas in vivo.
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PMID:Inducible nitric oxide synthase neutralizes carbamoylating potential of 1,3-bis(2-chloroethyl)-1-nitrosourea in c6 glioma cells. 1125 58


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