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

Activated inflammatory leukocytes generate a variety of reactive oxygen and nitrogen species (RONS) that may have roles in mutagenesis and carcinogenesis. The purpose of the present study was to explore the relationship between inflammatory leukocyte activation and mutagenesis using co-culture systems. We investigated the mutagenic potentials of 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated differentiated HL-60 (human promyelocytic leukemia cells), and RAW 264.7 cells (murine macrophages) stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma by co-culturing each cell line with AS52 cells, a transgenic Chinese hamster ovary cell line. HL-60 cells rapidly generated superoxide (O(2)(-)) 15 min to 1 h (peak at 30 min) following TPA stimulation. RAW 264.7 cells stimulated with LPS and IFN-gamma produced O(2)(-), nitric oxide (NO) and peroxynitrite (ONOO(-)) continuously for 5-25 h. There was a 2.0-fold increase in the mutation frequency of the gpt gene in AS52 cells co-cultured with TPA stimulated HL-60 cells, when compared with non-treated cells. Importantly, this increase in mutation frequency was significantly suppressed by antioxidants, such as superoxide dismutase (SOD) and diphenylene iodonium (DPI), an NADPH oxidase inhibitor (inhibition rates: IRs = 18.2 and 35.1%, respectively). Similarly, co-culture of AS52 cells with LPS/IFN-gamma-stimulated RAW 264.7 cells also increased the mutation frequency of the gpt gene by 2.6-fold, and this increase in mutation frequency was suppressed by SOD, DPI and N(5)-(1-iminoethyl)-L-ornithine dihydrochloride (L-NIO), an specific iNOS inhibitor (IRs = 58.3, 70.8 and 70.8%, respectively). In co-culture experiments, activated HL-60 and RAW 264.7 cells increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in AS52 cells when compared with non-treated controls (1.7- and 1.6-fold, respectively). Treatment of AS52 cells with hydrogen peroxide (H(2)O(2), 100 micro M), ONOO(-) (100 micro M) and SIN-1 (100 micro M), a ONOO(-) generator, also increased the mutation frequency of the gpt gene (4.6-, 5.4- and 2.8-fold, respectively). Taken together, these results support the hypothesis that RONS, derived from activated inflammatory leukocytes, are mutagenic in the biological systems, and that RONS generation inhibitors are potentially anti-mutagenic, and thus may be useful in cancer preventive strategies.
Carcinogenesis 2003 Feb
PMID:Mutagenicity of reactive oxygen and nitrogen species as detected by co-culture of activated inflammatory leukocytes and AS52 cells. 1258 72

IFN-gamma contributes to the rejection of transplantable tumors and the inhibition of methylcholanthrene (MCA)-induced carcinogenesis by different mechanisms. In most tumor transplantation models, tumor rejection requires IFN-gamma receptor expression by host cells, but not by tumor cells. IFN-gamma produced by either CD4+ or CD8+ T cells acts on non-hematopoietic tumor stroma cells and, either directly or indirectly, induces angiostasis. This prevents rapid tumor burden and allows residual tumor cells to be eliminated. In some models, IFN-gamma also contributes to the destruction of existing tumor blood vessels. During MCA-induced tumorigenesis IFN-gamma is involved in the inhibition of MCA diffusion by encapsulation and reduction of DNA damage. This mechanism may primarily protect tissue from damage and simultaneously inhibit tumor development.
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PMID:The role of IFN-gamma in tumor transplantation immunity and inhibition of chemical carcinogenesis. 1263 63

We have demonstrated previously that suppression of some or all of the IFN-stimulated gene factor 3 (ISGF-3) proteins in skin squamous cell carcinomas is an early event in squamous skin carcinogenesis. This finding led to the hypothesis that suppressed expression of ISGF-3 proteins may lead to reduced IFN responsiveness, which in turn may contribute to skin malignancy by conferring a growth and/or survival advantage. To test this hypothesis, we have developed a skin cell-based model for inhibiting the IFN-alpha signaling pathway through the forced expression of a dominant negative-acting signal transducer and activator of transcription 2 (dnSTAT2) protein. Expression of dnSTAT2 suppressed cell growth inhibition with a pharmacologically achievable concentration (100 IU/ml) of IFN-alpha in the IFN-alpha-sensitive skin squamous cell carcinoma cell line SRB12-p9. dnSTAT2 also suppressed the IFN-alpha-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2, which are early events following IFN-alpha treatment, but did not suppress the IFN-gamma-induced phosphorylation of STAT1. Finally, the dnSTAT2 protein suppressed the up-regulation of several IFN-alpha-inducible genes that were identified in this system by cDNA microarray screening. We conclude that the cell growth-inhibitory effect of IFN-alpha in skin cells requires an intact STAT2 protein and is therefore mediated by the ISGF-3 complex. These results support STAT2 as an important molecular target for skin cancer chemoprevention. Furthermore, we propose that these dnSTAT2-expressing cells provide a novel in vitro model for the study of type I IFN action in human skin cells.
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PMID:Dominant negative signal transducer and activator of transcription 2 (STAT2) protein: stable expression blocks interferon alpha action in skin squamous cell carcinoma cells. 1274 7

Within 33 weeks of life, all 10 mammary glands of virgin BALB/c mice transgenic for the transforming rat HER-2/neu oncogene under the mammary tumor virus promoter (BALB-neuT mice) progress from atypical hyperplasia to invasive palpable carcinoma. Repeated DNA vaccination with plasmids coding for the extracellular and transmembrane domain of the protein product of rat HER-2/neu (r-p185(neu)) delayed tumor onset and reduced tumor multiplicity, but this protection eventually declined, and few mice were tumor free at 1 year of age. Association of plasmid vaccination with administration of soluble mouse LAG-3 (lymphocyte activation gene-3/CD223) generated by fusing the extracellular domain of murine LAG-3 to a murine IgG2a Fc portion (mLAG-3Ig) elicited a stronger and sustained protection that kept 70% of 1-year-old mice tumor free. Moreover, this combined vaccination, which was performed when multiple in situ carcinomas were already evident, extended disease-free survival and reduced carcinoma multiplicity. Inhibition of carcinogenesis was associated with markedly reduced epithelial cell proliferation and r-p185(neu) expression, whereas the few remaining hyperplastic foci were heavily infiltrated by reactive leukocytes. A stronger and enduring r-p185(neu)-specific cytotoxicity, a sustained release of IFN-gamma and interleukin 4, and a marked expansion of both CD8(+)/CD11b(+)/CD28(+) effector and CD8(+)/CD11b(+)/CD28(-) memory effector T-cell populations were induced in immunized mice. This combined vaccination also elicited a quicker and higher antibody response to r-p185(neu), as well as an early antibody isotype switch. These data suggest that the appropriate costimulation provided by mLAG-3Ig enables DNA vaccination to establish an effective protection, probably by enhancing cross-presentation of the DNA coded antigen.
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PMID:LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice. 1275 Feb 75

Resveratrol, synthesized in dietary plants and contained in wine, has been reported to play a beneficial role in certain cardiovascular regulatory mechanisms and to inhibit carcinogenesis by activating immune and inflammatory responses and apoptosis. The object of this study was to elucidate the "in vitro" effects of different concentrations of resveratrol (10(-4), 10(-5), and 10(-7) M) on human peripheral blood mononuclear cell (PBMC) proliferation and cytokine release. Spontaneous PBMC proliferation was unaffected by resveratrol, while the compound at 10(-4) M inhibited (69%) the PHA-stimulated PBMC proliferation. The proliferation stimulation index (ie, the ratio of PHA-stimulated PBMC proliferation/spontaneous PBMC proliferation) of cultures containing 10(-4) M resveratrol was very low in relation to the control, while the proliferation stimulation index values at 10(-5) and 10(-7) M were similar and slightly higher (without statistical significance), respectively. At 10(-4) M, resveratrol strongly inhibited PHA-stimulated IFN-gamma and TNF-alpha release from PBMC, but it did not cause inhibition at 10(-5) or 10(-7) M. The concomitant immune effects of resveratrol on PBMC proliferation and release of IFN-gamma and TNF-alpha may be explained by an inhibitory effect on transcription factor NF-kappaB. This study suggests that resveratrol, which is typically present in red wine at about 10(-5) M, is unlikely to cause inhibitory immune effects. However, a stimulatory effect of low concentrations of resveratrol on the immune system cannot be excluded.
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PMID:Effects of resveratrol on lymphocyte proliferation and cytokine release. 1281 28

Recent studies have revealed significant efficacy of the marine sponge glycolipid, alpha-galactosylceramide (alpha-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of alpha-GalCer to prevent tumor development had never, to our knowledge, been evaluated in mouse models of chemical- and oncogene-dependent carcinogenesis. In this study, we demonstrate that long-term administration of soluble alpha-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2/neu transgenic mice, and spontaneous sarcomas in p53-/- mice. Weekly treatment of mice with alpha-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-gamma and IL-4 concentrations. Consistent with the antimetastatic activity of alpha-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-gammaand tumor necrosis factor-related apoptosis-inducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1+alphabetaTCR+ cell-based immune therapy can inhibit primary tumorigenesis.
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PMID:Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. 1286 93

Inulin, an active component of Chicorium intybus root, has been shown to stimulate the growth of bifidobacteria, and inhibit colon carcinogenesis. NO mediates a number of the host-defense functions of activated macrophages, including antimicrobial and tumoricidal activity. We examined the effect of inulin on the synthesis of NO in RAW 264.7 cells. Inulin alone had no effect, whereas inulin with IFN-gamma synergistically increased the NO production and inducible NO synthase (iNOS) expression in RAW 264.7 cells. Synergy between IFN-gamma and inulin was mainly dependent on inulin-induced TNF-alpha secretion. Also, protein kinase C (PKC)-alpha was involved in the inulin-induced NO production. Inulin-mediated NO production was inhibited by the protein tyrosine kinase (PTK) inhibitor, tyrphostin AG126. Since iNOS gene transcriptions have been shown to be under the control of the NF-kappaB/Rel family of transcription factors, we assessed the effect of inulin on NF-kappaB/Rel using an EMSA. Inulin produced strong induction of NF-kappaB/Rel binding, whereas AP-1 binding was slightly induced in RAW 264.7 cells. Inulin stimulated phosphorylation and degradation of IkappaB-alpha. These results suggest that in IFN-gamma-primed RAW 264.7 cells inulin might stimulate NO synthesis via activation of PKC-alpha and PTK, resulting in the activation of NF-kappaB.
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PMID:Inulin stimulates NO synthesis via activation of PKC-alpha and protein tyrosine kinase, resulting in the activation of NF-kappaB by IFN-gamma-primed RAW 264.7 cells. 1455 11

Interferon-gamma-receptor (IFN-gammaR)-deficient mice are more susceptible to tumor induction by methylcholanthrene (MCA) in comparison to control littermates. The cellular source of IFNgamma is not known, but the absence of T cells does not significantly increase the incidence of MCA-induced tumors. However, it appears that the presence of T cells in combination with unknown, perhaps environmental, factors can decrease MCA-induced tumor incidence, indicating that IFN-gamma of unknown origin contributes to the protective response. The current knowledge of cancer biology, immune regulation, and tumor-promoting effects of inflammation are difficult to reconcile with the concept of immune surveillance against non-virus-associated cancer. Analysis of the primary MCA-treated mouse indicates, as one protective mechanism, a tissue repair response against MCA-induced damage, in the course of which MCA is encapsulated and persists for long time in tumor-free mice, termed foreign-body reaction. The protection from DNA damage could simultaneously diminish tissue injury and malignant transformation. We argue that inhibition of MCA-induced carcinogenesis is mechanistically different from tumor transplantation immunity and that a longer latency in MCA-treated mice is unlikely due to T cell-mediated tumor recognition and selection of less immunogenic variants. We discuss that the IFNgammaR-dependent mechanism against MCA is unrelated to the original concept of T cell-mediated immune surveillance and that the increased spontaneous tumor incidence observed in some immune-deficient mice is likely to be explained by opportunistic infection and tumor-promoting chronic inflammation.
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PMID:Chemical carcinogens as foreign bodies and some pitfalls regarding cancer immune surveillance. 1471 Sep 51

While much experimental data shows that vaccination efficiently inhibits a subsequent challenge by a transplantable tumor, its ability to inhibit the progress of autochthonous preneoplastic lesions is virtually unknown. In this article, we show that a combined DNA and cell vaccine persistently inhibits such lesions in a murine HER-2/neu mammary carcinogenesis model. At 10 weeks of age, all of the ten mammary gland samples from HER-2/neu-transgenic mice displayed foci of hyperplasia that progressed to invasive tumors. Vaccination with plasmids coding for the transmembrane and extracellular domain of rat p185neu followed by a boost with rp185neu+ allogeneic cells secreting IFN-gamma kept 48% of mice tumor free. At 22 weeks, their mammary glands were indistinguishable from those of 10-week-old untreated mice. Furthermore, the transcription patterns of the two sets of glands coincided. Of the 12,000 genes analyzed, 17 were differentially expressed and related to the antibody response. The use of B cell knockout mice as well as the concordance of morphologic and gene expression data demonstrated that the Ab response is the main mechanism facilitating tumor growth arrest. This finding suggests that a new way can be found to secure the immunologic control of the progression of HER-2/neu preneoplastic lesions.
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PMID:Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions. 1499 Oct 69

IFN regulatory factor-1 (IRF-1) is a critical effector molecule in IFN signaling and acts as a tumor suppressor and tumor susceptibility gene. IL-12 is a key factor in the induction of innate resistance and generation of Th1 cells and CTL. Our recent study has revealed an intimate relationship between IRF-1 and IL-12 in that IRF-1 regulates the production of IL-12 by selectively controlling transcriptional activation of IL-12 p35 gene. In this work, we find that IRF-1-deficient mice are highly susceptible to N-methyl-N-nitrosourea (MNU)-induced T lymphomas. This susceptibility is associated with strong defects in the expression of IL-12, lymphotoxin (LT)beta, and IFN-gamma. Consistently, IL-12 p35(-/-), IFN-gamma(-/-), and LTbeta(-/-) mice are also highly vulnerable to MNU-induced carcinogenesis. Administration of rIL-12 to IRF-1(-/-) mice restores normal expression of LTbeta and IFN-gamma, and significantly enhances the ability of IRF-1(-/-) mice to resist MNU-induced pathogenesis. This strongly suggests an IRF-1/IL-12/IFN-gamma regulatory axis in tumor surveillance. By DNA microarray analysis, we comprehensively identify differences and patterns in gene expression in splenocytes of wild-type (WT) vs IRF-1(-/-) mice challenged with MNU. This study contributes to efforts to elucidate the cellular/molecular mechanisms and the downstream players involved in IRF-1-mediated host defense against lymphoproliferative malignancies.
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PMID:Role of IFN regulatory factor-1 and IL-12 in immunological resistance to pathogenesis of N-methyl-N-nitrosourea-induced T lymphoma. 1524 Jul 9


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