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)

A variety of chemicals can adversely affect the immune system and influence tumor development. The modifying potential of chemical carcinogens on the lymphoid organs and cytokine production of rats submitted to a medium-term initiation-promotion bioassay for carcinogenesis was investigated. Male Wistar rats were sequentially initiated with N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4hydroxybutyl)nitrosamine (BBN), dihydroxy-di-n-propylnitrosamine (DHPN), and 1,2-dimethylhydrazine (DMH) during 4 weeks. Two initiated groups received phenobarbital (PB) or 2-acetylaminofluorene (2-AAF) for 25 weeks and two noninitiated groups received only PB or 2-AAF. A nontreated group was used as control. Lymphohematopoietic organs, liver, kidneys, lung, intestines, and Zymbal's gland were removed for histological analysis. Interleukin (IL)-2, IL-12, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), IL-10, and transforming growth factor beta1 (TGF-beta1) levels were determined by ELISA in spleen cell culture supernatants. At the fourth week, exposure to the initiating carcinogens resulted in cell depletion of the thymus, spleen and bone marrow, and impairment of IL-2, IL-12, and IFN-gamma production. However, at the 30th week, no important alterations were observed both in lymphoid organs and cytokine production in the different groups. The results indicate that the initiating carcinogens used in the present protocol exert toxic effects on the lymphoid organs and affect the production of cytokines at the initiation step of carcinogenesis. This early and reversible depression of the immune surveillance may contribute to the survival of initiated cells facilitating the development of future neoplasia.
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PMID:Chemically induced immunotoxicity in a medium-term multiorgan bioassay for carcinogenesis with Wistar rats. 1473 94

NNK, a nicotine-derived nitrosamine, is a potent lung carcinogen that generates electrophilic intermediates capable of damaging DNA. The effects of NNK on the immune response, which may facilitate lung carcinogenesis, are poorly understood. Alveolar macrophages (AM), a key cell in the maintenance of lung homeostasis, metabolize NNK via two major metabolic activation pathways: alpha-methylhydroxylation and alpha-methylenehydroxylation. We have shown previously that NNK inhibits the production of interleukin-12 (IL-12) and tumor necrosis factor (TNF), but stimulates the production of IL-10 and prostaglandin E(2) (PGE(2)) by AM. In the present study, we investigated the contribution of each activation pathway in the modulation of AM function. We used two precursors, 4-[(acetoxymethyl)-nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) and N-nitro(acetoxymethyl)methylamine (NDMAOAc), which generate the reactive electrophilic intermediates [4-(3-pyridyl)-4-oxo-butanediazohydroxide and methanediazohydroxide, respectively] in high yield and exclusively. Rat AM cell line, NR8383, was stimulated and treated with different concentrations of NNKOAc or NDMAOAc (12, 25 and 50 microM). Mediator release was measured in cell-free supernatants. NNKOAc significantly inhibited the production of IL-10, IL-12, TNF and nitric oxide but increased the release of PGE(2) and cyclooxygenase-2 expression suggesting that the alpha-methylhydroxylation pathway might be responsible for NNK modulation of AM cytokine release. In contrast, NDMAOAc did not modulate AM mediator production. However, none of these precursors, alone or in combination, could explain the stimulation of AM IL-10 production by NNK. Our results suggest that the alpha-methylhydroxylation of NNK leading to DNA pyridyloxobutylation also modulates cytokine production in NNK-treated AM.
Carcinogenesis 2004 Jun
PMID:Cytokine production by alveolar macrophages is down regulated by the alpha-methylhydroxylation pathway of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). 1476 58

Improvement of immunotherapy-based protocols in cancer requires a better understanding of tumor microenvironment and tumor-host interaction. Stromal and immune cells and molecules such as cytokines, chemokines, growth factors and metalloproteases mediate tumor-host interaction determining, at least in part, tumor development. In the present study, we used an immunohistochemical approach to explore leukocyte sub-populations, cytokine profiles and costimulatory molecule expression in rat N -Nitrosomethylurea (NMU)-induced breast tumors. Our results show a strong leukocyte infiltration mainly composed of macrophages and TCR alphabeta positive T cells. We observed a weak expression of costimulatory molecules (CD80, CD86) and an absence of inflammatory cytokines (IFNgamma, TNFalpha, IP-10) and lymphocyte activation markers (CD25). Interestingly, this immunosuppressed status could be a consequence of IL-10 expression by malignant cells, as demonstrated by immunohistology and western blot analysis, which seems to be an early event during mammary carcinogenesis. Analysis of a cell line derived from an NMU-induced rat breast tumor showed that this cell line also expresses IL-10. This study shows that the NMU model of rat breast cancer could be used to evaluate different immune based therapies as well as to study the role of IL-10 in breast cancer. Furthermore, this rat breast cancer model shows an immunohistological profile similar to that found in human cancer and the fact that it develops like spontaneously arising malignancies make it interesting as a cancer model in immunobiology.
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PMID:Immunobiological characterization of N -nitrosomethylurea-induced rat breast carcinomas: tumoral IL-10 expression as a possible immune escape mechanism. 1499 41

Helicobacter pylori infection and the cytokine-mediated inflammatory responses play important roles in gastric cancer pathogenesis. This case control study was conducted to assess the association between genetic polymorphisms in interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor alpha (TNFalpha), which are involved in H.pylori infection, and risk of gastric cancer. Genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 250 incident cases with gastric cancer and 300 controls recruited in Northern China. Serum levels of anti-H.pylori IgG and IgA were measured by enzyme-linked immunosorbent assay to indicate H.pylori infection. We found that the risk of gastric cancer was significantly elevated in subjects with the IL-8-251 AA [adjusted odds ratio (OR) 2.02; 95% confidence interval (CI) 1.27-3.21] or IL-10-1082 G (OR 2.02; 95% CI 1.24-3.29) or TNFalpha-308 AG (OR 1.81; 95% CI 1.04-3.14) genotype. An elevated risk of gastric cancer was observed in subjects with H.pylori infection and the IL-8-251 AA genotype (OR 2.54; 95% CI 1.38-4.72) or IL-10-1082 G carriers (OR 2.62; 95% CI 1.42-4.93). An increased OR was also suggested for IL-1B-31 and TNFalpha-238, but confidence intervals included the null value. There was no evidence of increased risk for any of the other polymorphisms evaluated. These findings suggest that genetic polymorphisms in IL-8, IL-10 and TNFalpha may play important roles in developing gastric cancer in the Chinese population.
Carcinogenesis 2005 Mar
PMID:Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. 1557 81

Probiotics (PRO) are known to modulate immunity in animals and human subjects and to inhibit colon carcinogenesis in experimental models, but the effects of synbiotics (SYN) are not well understood. Therefore, the effects of PRO (Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12), PRE (inulin-based enriched with oligofructose, 100 g/kg) and SYN (combination of PRO and PRE) on the immune system of rats were investigated in the azoxymethane (AOM)-induced colon cancer model. After 33 weeks, rats with and without AOM treatment were killed and immune cells were isolated from spleen, mesenterial lymph nodes (MLN) and Peyer's patches (PP). AOM treatment significantly reduced natural killer (NK) cell-like cytotoxicity in control rats and in PRO- and PRE-supplemented rats. SYN supplementation prevented the AOM-induced suppression of NK cell-like cytotoxicity in PP compared with control rats (P<0.01). SYN and PRE supplementation stimulated IL-10 production in PP in these rats (P<0.01) and in MLN of rats not treated with AOM (P<0.05). Interferon-gamma production in PP was decreased by PRO supplementation (PRO and SYN groups combined; P<0.05). Proliferative responsiveness of lymphocytes (PP) from AOM-treated rats was suppressed in SYN-supplemented rats (P<0.01). Overall, SYN supplementation in carcinogen-treated rats primarily modulated immune functions in the PP, coinciding with a reduced number of colon tumours. PRE and PRO provided in combination as SYN may contribute to the suppression of colon carcinogenesis by modulating the gut-associated lymphoid tissue.
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PMID:Intestinal immunity of rats with colon cancer is modulated by oligofructose-enriched inulin combined with Lactobacillus rhamnosus and Bifidobacterium lactis. 1561 55

Evidence indicates that the testis possesses a reduced capacity to mount inflammatory and rejection responses, which undoubtedly contributes to the ongoing survival of the highly immunogenic germ cells. The contribution of local cytokine expression to this condition was investigated in adult male rats treated with lipopolysaccharide to induce inflammation. Cytokine mRNA and protein expression were determined in tissue extracts and fluids by Northern blot analysis, quantitative PCR, or RNAse protection assay and specific ELISAs. Testicular expression of the proinflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor-alpha was considerably attenuated compared with the liver (control tissue); in contrast, the testicular IL-6 response was enhanced. Expression of IL-10, a type 2 immunoregulatory cytokine, was similar in both testis and liver, whereas the immunoregulatory/anti-inflammatory cytokines transforming growth factor-beta(1) and activin A were constitutively elevated in both normal and inflamed testes. The IL-1beta and transforming growth factor-beta(1) proteins were present principally in their latent (inactive) forms, indicating that enzymic processing is an important control mechanism for these two cytokines within the testis. These data indicate that inflammatory and regulatory cytokine activity is regulated at both transcriptional and posttranslational levels in a testis-specific manner. It is concluded that a novel pattern of suppression of proinflammatory cytokine responses and normal or elevated expression of immunoregulatory cytokines may be responsible for reduced inflammatory responses and enhanced graft survival in the testis. These data have important implications for the understanding and treatment of male autoimmune infertility, testicular inflammation. and carcinogenesis.
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PMID:Cytokine profiles in the testes of rats treated with lipopolysaccharide reveal localized suppression of inflammatory responses. 1566 66

Chronic inflammation has been linked to carcinogenesis in various tissue sites. Barrett's oesophageal epithelium (BE) is a premalignant condition in which cyclooxygenase-2 (COX-2) levels are increased. However, it is not clear whether the primary stimulus for the high COX-2 levels is related to inflammation or malignancy. The effect of exogenous cytokines (IL-1beta, IL-10 and IL-13) on COX-2 expression was assessed by western blotting in three BE cancer cell lines (SEG-1, BIC-1 and OE33) and a squamous cancer cell line (OE21). Primary tissue was assessed from 17 patients with long BE segments, 13 oesophagitis, 30 oesophageal adenocarcinoma (EAC), and 40 normal oesophageal (NE) and duodenal (DU) controls. COX-2 protein expression was determined by western blotting and its tissue localization was examined using immunohistochemistry. COX-2 protein and the neutrophil marker myeloperoxidase (MPO) were quantified along BE segments. The leukocyte marker CD45 was used to identify any correlation between COX-2 expression and leukocyte cell distribution in EAC. IL-1beta induced COX-2 expression in SEG-1 cells (P < 0.05), whereas IL-10 and IL-13 had no effect. COX-2 protein levels were found to be increased in distal BE > proximal BE > oesophagitis > NE (P < 0.001). COX-2 expression in EAC was heterogeneous and the overall levels were not significantly increased. The increased COX-2 expression in distal BE was not associated with inflammation (MPO expression). In addition, there was no correlation between COX-2 and CD45 in AC. COX-2 protein expression in the oesophagus appears to be independent of the degree of inflammation.
Carcinogenesis 2005 Sep
PMID:Effect of inflammation on cyclooxygenase (COX)-2 expression in benign and malignant oesophageal cells. 1587 11

We performed this study to determine the role of polymorphisms of the IL-10 and TNF-alpha promoter genes in the carcinogenesis/pathogenesis of gastric cancer (GC) and peptic ulcer diseases (PUD) in Korea. A total of 232 patients with gastric diseases and 120 healthy controls were included. Polymorphisms of IL-10-1082/-592 gene and TNF-A-308 gene were genotyped by PCR-RFLP. There were no differences in genotypes and allele frequencies of IL-10 and TNF-A polymorphism between study group with GC or PUD and control group. In addition, there were no differences in genotypic frequencies according to H. pylori infection status, location of GC, and histologic type of GC. In conclusion, IL-10-1082/-592 and TNF-A-308 genetic polymorphisms may not be the important contributors to GC in Korea.
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PMID:Association of polymorphism of IL-10 and TNF-A genes with gastric cancer in Korea. 1597 25

Individuals with inflammatory bowel disease (IBD) are at increased risk of developing gastrointestinal cancer. Here, we have tested the possibility that chronic inflammation could trigger mutations. For this, we have used IL-10-deficient (IL-10-/-) mice, which spontaneously develop intestinal inflammation, in combination with a transgenic gpt gene and red/gam gene (gpt+IL-10-/-), which is a well-characterized mutation reporter locus. The total mutation frequency in the colon of gpt+IL-10-/- mice was about five times higher than that in normal gpt+IL-10+/+ mice. In the particular case of G:C to A:T transitions, the frequency of mutations in gpt+IL-10-/- mice was 4.1 times higher than that in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (approximately 10 times). The majority of the deletion or insertion mutations were observed in the monotonous base runs or adjacent repeats of short tandem sequences. In contrast, the frequency of large deletions, detected by loss of the Spi marker present in the red/gam transgene, was similar among the mouse strains. Finally, as a control, the mutation frequency in non-inflamed tissues, such as the liver, were similar between gpt+IL-10-/- mice and gpt+IL-10+/+ mice. Our data demonstrate that the chronic inflammatory environment in the colon promotes the generation of mutations.
Carcinogenesis 2006 May
PMID:IL-10 deficiency leads to somatic mutations in a model of IBD. 1640 68

Helicobacter pylori infection is an important risk factor for gastric cancer, but <3% of carriers of this organism will ever develop gastric cancer. Since inflammation plays a significant role in gastric carcinogenesis, it has been suggested that polymorphisms in genes involved in inflammatory response may partly explain why only a subgroup of patients infected with H. pylori develop gastric cancer. We compared relative frequencies of 17 single nucleotide polymorphisms (SNPs) in eight inflammation-related genes between 112 gastric cancer patients and 208 controls. Cases and controls were selected from a large cohort of Finnish male smokers who were recruited into the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The studied SNPs were IL-1A (-889 C/T), IL-1B (-511 C/T and -31 T/C), IL-6 (-174 G/C and -597 G/A), IL-8 (-251 T/A, +396 T/G and +781 C/T), IL-8RA (Ex2 +860 G/C), IL-8RB (Exon 3 +1235 T/C, Exon 3 +811 C/T, and Exon 3 +1010 G/A), IL-10 (-819 C/T, -592 C/A, -1082 A/G), and TNF A (-308 G/A, -238 G/A). We found no statistically significant association between any of these SNPs, or the number of pro-inflammatory polymorphisms, with risk of gastric cancer. Our results do not support the hypothesis that polymorphisms in genes involved in the inflammatory response confer differences in gastric cancer risk among different individuals.
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PMID:Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland). 1641 Oct 61


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