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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines can have both negative and positive effects on cells undergoing carcinogenesis. The promotion and progression phases of carcinogenesis may be affected by autocrine loops involving cytokines with growth factor activities such as IL-1, IL-2, low molecular weight B cell growth factor, TNF, IL-3, GM-CSF, M-CSF and IL-9. Aberrations in cytokine receptors such as the truncated EGF receptor present in v-erB promotes the growth of neoplastic cells. Aberrant signaling mechanisms, as found with spleen focus-forming virus, which mimics the ligand that activates the erythropoietin receptor, can also contribute to proliferation of preneoplastic and neoplastic cells. In contrast, cytokines such as interferons, LIF, TGF-beta, TNF and leukoregulin, with antiproliferative or differentiating activities, are sometimes capable of inhibiting carcinogenesis. Transfection of tumor cells with cytokine genes, such as IL-2, IL-4 and TNF, can cause suppression of in vivo tumor cell growth by mobilizing host immune and inflammatory cell responses. Thus cytokines and their receptors may play a direct role in early stages of tumor cell development and growth.
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PMID:Cytokines as positive and negative regulators of tumor promotion and progression. 132 42

In previous studies we showed that tumor-associated macrophages isolated from murine mammary tumors are mutagenic to bacteria and mammalian cells and thus may contribute to tumor progression. We reported previously, and confirm here, that inflammatory macrophages induce DNA strand breaks in cultured mammary tumor cells co-incubated at a 1:1 ratio for 1 h. This activity is prevented by inhibitors of arachidonate metabolism or the removal of H2O2 with catalase. In the present study, we show that two antibodies to recombinant murine tumor necrosis factor alpha (rMuTNFa)--a hamster monoclonal antibody (TN3-19.12) and a rabbit polyclonal antibody (Genzyme)--partially protect tumor cells from DNA strand breaks induced by elicited but not resident peritoneal macrophages. Antibody protection was reversed upon the addition of excess exogenous rMuTNFa. Purified rMuTNFa alone was unable to induce DNA strand breaks in the absence of macrophages, indicating that TNFa is necessary but not sufficient to mediate damage. Tumor target cells were completely resistant to the cytotoxic effects of rMuTNFa in the absence of actinomycin D and relatively resistant (in comparison to WEHI 164 clone 13 cells) in its presence. The incomplete protection seen with either catalase or anti-TNF suggests that macrophage-released TNFa, in the presence of other factors, induces non-cytotoxic DNA effects in tumor cells.
Carcinogenesis 1992 Jan
PMID:The role of macrophage-derived TNFa in the induction of sublethal tumor cell DNA damage. 173 75

The proinflammatory effects of passive inhalation of cigarette smoke were investigated by exposing a total of 16 healthy, young nonsmokers (mean age 29 +/- 1.4 yr, 11 women and five men) to actively smoking individuals in a poorly-ventilated room. Neutrophil functions were measured before and after 3 h of exposure to cigarette smoke. Passive cigarette smoking was associated with increased leukocyte counts (mean increase 33%, p less than 0.005), chemotaxis (57%, p less than 0.001), and release of reactive oxidants (71%, p less than 0.005) by stimulated neutrophils. These results were confirmed in a second study designed to eliminate the possible complicating effects of serial venepuncture. Plasma concentrations of the proinflammatory cytokines interleukin-1 (IL-1) alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) were not affected by passive smoking. These results indicate that inhalation of sidestream tobacco smoke promotes systemic priming of neutrophils. These potentially proinflammatory events may induce oxidant-mediated tissue damage and carcinogenesis in the lungs of passive smokers.
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PMID:Passive smoking by humans sensitizes circulating neutrophils. 189 96

Recent studies have demonstrated that nitric oxide (NO)-derived N-nitrosating agents may promote mutagenesis and carcinogenesis from the nitrosative deamination of DNA bases via the formation of nitrosamine intermediates. The objective of this study was to determine if pleural mesothelial cells (PMC) stimulated with proinflammatory cytokines could promote the N-nitrosation of a primary aromatic amine via the L-arginine-dependent formation of NO-derived N-nitrosation agents. N-nitrosating activity was determined by measuring the N-nitrosation of a model amine, 2,3-diaminonapthalene, to yield its fluorescent triazole (1-naptho-2,3-triazole) derivative. Results show that specific combinations of TNF, IL-1, interferon gamma, and LPS significantly increased N-nitrosating activity. There was a significant positive correlation between nitrite plus nitrate and triazole production. Triazole formation was inhibited by NG-nitro-L-arginine methyl ester, suggesting that triazole was derived from L-arginine-dependent formation of NO. These data indicate that PMC have the capacity to promote the N-nitrosation of primary aromatic amines via the formation of NO.
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PMID:Nitric oxide-dependent N-nitrosating activity of rat pleural mesothelial cells. 749 43

Tumor necrosis factor alpha (TNF alpha), a pleiotrophic cytokine present in atherosclerotic lesions, caused a dose-dependent and persistent reduction in gap junctional intercellular communication (GJIC) between primary human smooth muscle cells in vitro. A continuous presence of TNF alpha was required for this persistent inhibition. Pretreatment of smooth muscle cells with ascorbic acid, alpha-tocopherol or glutathione prevented this inhibition of GJIC by TNF alpha. The persistent blockage of GJIC by continuous exposure to TNF alpha suggests that TNF alpha may share some mechanistic similarities with exogenous tumor promoters. Furthermore, this reduction in GJIC by TNF alpha may provide an additional link between the processes of atherosclerosis and carcinogenesis. The protection afforded by antioxidant compounds suggests a role for active oxygen species in the promotion stage of atherosclerosis.
Carcinogenesis 1995 Sep
PMID:Inhibition of gap junctional intercellular communication between primary human smooth muscle cells by tumor necrosis factor alpha. 755 55

Tautomycin isolated from Streptomyces spiroverticillatus is an inhibitor of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphorylation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications of tautomycin (30 micrograms, 40 nmol/application) did not induce tumor promotion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 microgram, 1.2 nmol/application) as a control induced tumor promotion strongly. As for mucosa of rat glandular stomach, tautomycin induced ornithine decarboxylase 4 h after intubation into the stomach. The tumor-promoting activity of tautomycin was next studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Administration of tautomycin in the diet (1 mg rat-1 day-1), from week 9 to week 52 of the experiment, inhibited rather than enhanced tumor development in the glandular stomach initiated with MNNG. The percentages of tumor-bearing rats of the groups treated with MNNG plus tautomycin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respectively in week 52. The reason for the absence of tumor-promoting activity of tautomycin was studied in relation to tumor necrosis factor alpha (TNF alpha), an endogenous tumor promoter. We found that tautomycin neither enhanced TNF alpha mRNA expression in mouse skin nor induced TNF alpha release in a human stomach cancer cell line (KATO III cells), whereas okadaic acid did both. These results indicate that not all inhibitors of protein phosphatases are tumor promoters, and suggest that tumor promotion of the okadaic acid class of compounds is mediated by TNF alpha.
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PMID:Tautomycin: an inhibitor of protein phosphatases 1 and 2A but not a tumor promoter on mouse skin and in rat glandular stomach. 755 47

The direct effect of nicotine on the expression of receptors for the tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta) and the internalization, intracellular distribution and stability of these growth factors in cervical cancer cell line SiHa was studied. Nicotine at concentrations in the range 0.05-0.25% inhibited cell growth and it exerted strong apoptotic and cytolytic effects at concentrations above 0.5%. Nicotine at 0.1% stabilized and protected from degradation [125I]TNF alpha and [125I]TGF beta internalized by cervical cancer SiHa cell line. In the absence of nicotine, [125I]TNF alpha and [125I]TGF beta were internalized during the first hour of incubation and localized mainly in the cytoplasm and in smaller amounts in the nucleus. After 1 day of cell exposure to growth factors, only traces of radioactivity were detected inside the cells, which indicated that both growth factors were rapidly degraded. In the presence of nicotine, both [125I]TNF alpha and [125I]TGF beta were detected in high quantities and in a non-degraded form in the cytoplasm and chromatin during 5 days of incubation. In addition to the lack of growth factor degradation, the presence of nicotine induced a nuclear accumulation of growth factors, with up to 37% of the internalized [125I]TGF beta being in the chromatin. An increased intracellular accumulation of [125I]TNF alpha and [125I]TGF beta in cells exposed to nicotine occurred without changes in expression of the cell surface receptors. Nuclear accumulation of TGF beta was followed by increased RNA synthesis and a switch from the growth-promoting action of TGF beta to the strong growth inhibitory effect. Inhibition of the lysosomal degradation of growth factors by nicotine is discussed as a potential mechanism of tobacco-induced carcinogenesis.
Carcinogenesis 1994 Sep
PMID:Growth factor-mediated mechanisms of nicotine-dependent carcinogenesis. 792 76

Scatter factor (SF) (also known as hepatocyte growth factor [HGF]) is a fibroblast-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. SF may play major roles in development, repair, and carcinogenesis. However, the physiologic signals that regulate its production are not well delineated. We found that various human tumor cell lines that do not produce SF secrete factors that stimulate SF production by fibroblasts, suggesting a paracrine mechanism for regulation of SF production. Conditioned medium from these cell lines contained two distinct scatter factor-inducing factor SF-IF activities: a high molecular weight (> 30 kD), heat sensitive activity and a low molecular weight (< 30 kD) heat stable activity. Further studies revealed that SF-producing fibroblasts also secrete factors that stimulate their own SF production. We characterized the < 30-kD SF-IF activity from ras-3T3 (clone D4), a mouse cell line that overproduces both SF and SF-IF. The < 30-kD filtrate from ras-3T3 conditioned medium induced four- to sixfold increases in expression of SF biologic activity, immunoreactive protein, and mRNA by multiple SF-producing fibroblast lines. Ras-3T3 SF-IF activity was stable to boiling, extremes of pH, and reductive alkylation, but was destroyed by proteases. We purified ras-3T3 SF-IF about 10,000-fold from serum-free conditioned medium by a combination of ultrafiltration, cation exchange chromatography, and reverse phase chromatography. The purified protein exhibited electrophoretic mobility of about 12 kD (reduced) and 14 kD (nonreduced) by SDS-PAGE. The identity of the protein was verified by elution of biologic activity from gel slices. Purified SF-IF stimulated SF production in a physiologic concentration range (about 20-400 pM). Its properties and activities were distinct from those of IL-1 and TNF, two known inducers of SF production. We suggest that SF-IF is a physiologic regulator of SF production.
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PMID:Regulation of scatter factor production via a soluble inducing factor. 792 65

It is generally accepted that asbestos exposure causes pulmonary fibrosis and carcinogenesis. Several studies have suggested that TNF alpha is produced principally by mononuclear phagocytes and that it may play a role in inflammation, fibrosis and anti-tumor activity. We studied TNF alpha production by alveolar macrophages and the TNF alpha concentration in bronchoalveolar lavage fluid harvested from asbestos-exposed subjects and healthy controls. TNF alpha production by alveolar macrophages was significantly higher in the asbestos-exposed subjects than in healthy controls (3696 +/- 1606, 1938 +/- 753 pg/ml; p < 0.01). The period from first exposure correlated inversely with TNF alpha production (r = -0.6; p < 0.05). The TNF alpha concentration in bronchoalveolar lavage fluid was also significantly higher in the asbestos-exposed subjects than in healthy controls. These results suggest that abnormal TNF alpha production by alveolar macrophages may be related to fibrosis and carcinogenesis due to asbestos.
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PMID:[Tumor necrosis factor alpha in bronchoalveolar lavage fluid and its production by alveolar macrophages with asbestos exposure]. 818 39

Among epidermal cytokines, IL-1 and TNF alpha are involved in inflammatory skin reactions and suspected of modulation by immunosuppressive treatment (e.g., cyclosporin A, CsA) or UVB-irradiation, 2 mediators probably being involved in epithelial carcinogenesis. We evaluated the effects of 8 micrograms/ml CsA and 100 J/m2 UVB-irradiation on the production and secretion of IL-1 and TNF alpha on normal human epidermal keratinocytes (NHK) and epidermal keratinocyte cell lines either spontaneously transformed (HaCaT) or transformed by human papillomavirus (HPV) type 16 or 18 (EK 16 and EK18), by using ELISA test. Normal and immortalized keratinocytes constitutively produced and released IL-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1RA) but IL-1 synthesis by NHK was significantly higher than by cell lines. All the cells spontaneously excreted low amounts of TNF alpha. Different responses to treatments were evidenced between NHK and cell lines. CsA modified significantly the production and secretion of IL1 in most cells whereas slight changes were observed with TNF alpha secretion. UVB irradiation had no effect on the intracellular IL1 pool of any cells but increased the release of IL1 and TNF alpha. The association CsA-UVB did not result in additive effects on synthesis and secretion of IL1; the release of TNF alpha by the cells remained poor except for EK18 cells. Taken together, these results show that, in immortalized keratinocytes, the IL-1 and TNF alpha expression was differently affected by treatments with CsA and/or UVB-irradiation as compared to NHK. In addition, spontaneously transformed keratinocytes, HaCaT, reacted differently from HPV-transformed keratinocytes, EK16 and EK18.
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PMID:Differences in responses of interleukin-1 and tumor necrosis factor alpha production and secretion to cyclosporin-A and ultraviolet B-irradiation by normal and transformed keratinocyte cultures. 906 3


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