Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clear (CleA) and cloudy (CloA) apple juices containing different amounts of analyzed procyanidins and pectin were investigated for preventive effects of colon cancer and underlying molecular mechanisms in F344 rats given intraperitoneal injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt) once a week for 4 weeks. Rats received either water (Cont), CleA or CloA (ad libitum) for 7 weeks starting 1 week before the first DMH injection. CloA inhibited DMH induced genotoxic damage in mucosa cells of the distal colon compared with Cont as investigated by single-cell microgel electrophoresis assay. The mean tail intensity in mucosa cells of DMH-treated controls (Cont/DMH: 6.1+/-0.9%) was significantly reduced by CloA (2.4+/-0.8%; P<0.01) but not by CleA intervention (4.1+/-1.2%; P>0.05). The crypt cell proliferation index induced by DMH (Cont/NaCl: 10.0+/-0.7%; Cont/DMH: 19.9+/-1.0%; P<0.001) was significantly decreased by CleA (15.7+/-0.7%; P<0.001) and CloA intervention (11.9+/-0.4%; P<0.001). CloA but not CleA significantly reduced the number of large aberrant crypt foci (ACF) consisting of more than four aberrant crypts (AC) (Cont/DMH: 37.4+/-5.4; CleA/DMH: 32.8+/-4.4, P>0.05; CloA/DMH: 18.8+/-2.5 ACF; P<0.05) and the overall mean ACF size in the distal colon (Cont/DMH: 2.31+/-0.09; CleA/DMH: 2.27+/-0.05; CloA/DMH: 2.04+/-0.03 AC/ACF; P<0.05). After treatment with DMH and/or apple juices there were no changes in transcript levels of colonic cyclooxygenase isoforms (COX-1, COX-2) or glutathione-associated enzymes (GST-M2, gamma-GCS, GST-P), the splenocyte natural killer cell activity and plasma antioxidant status. However, CloA but not CleA prevented the DMH-induced reduction of splenocyte CD4/CD8 (T-helper cells to cytotoxic lymphocytes) ratio. Since both formulations contained comparable concentrations and types of monomeric polyphenols, complex polyphenols or non-polyphenolic compounds, such as pectin might be responsible for the stronger cancer-preventive effect by CloA.
Carcinogenesis 2005 Aug
PMID:Cloudy apple juice decreases DNA damage, hyperproliferation and aberrant crypt foci development in the distal colon of DMH-initiated rats. 1580 99

Reported herein is a rare case of malignant T-cell lymphoma of the thyroid gland that developed in a 71-year-old woman with a past history of chronic thyroiditis. The chief complaints were rapidly growing neck mass, weight loss and hoarseness. Presence of abnormal lymphoid cells in the peripheral blood, and an increase in anti-microsome antibodies and anti-thyroglobulin antibodies were found on preoperative laboratory tests. A diagnosis of suspicious malignant lymphoma of the thyroid gland accompanied by Hashimoto's thyroiditis was made, and a total thyroidectomy was performed. Histological examination revealed diffuse small lymphocytic infiltration in the thyroid gland associated with Hashimoto's thyroiditis. Immunohistochemical examination showed that the small lymphocytes were positive for T-cell markers with CD4 predominance. Southern blot analysis of tumor specimens revealed a monoclonal T-cell receptor gene rearrangement. Peripheral T-cell lymphoma was diagnosed. No adjuvant therapy was performed because of the tumor stage and its subtype. The patient is well with no recurrence or metastasis 25 months after the surgical removal of the thyroid. The present case suggests that Hashimoto's thyroiditis might play an important role in the carcinogenesis of thyroid lymphoma not only of B-cell lineage but also of T-cell lineage.
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PMID:Malignant T-cell lymphoma of the thyroid gland associated with Hashimoto's thyroiditis. 1598 18

Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL-2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM-CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL-4, IL-10, or IFN-gamma by PHA-activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM-CSF secretion that may be associated with chronic inflammation.
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PMID:Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. 1646 32

Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage. DNA double-strand breaks (DSB) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. DSB may lead to chromosome aberrations, apoptosis and hematopoietic progenitor cell suppression. We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity. We analyzed one or more single nucleotide polymorphisms (SNPs) in each of seven candidate genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4) in a study of 250 workers exposed to benzene and 140 controls in China. Four SNPs in WRN (Ex4 -16 G > A, Ex6 +9 C > T, Ex20 -88 G > T and Ex26 -12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) were associated with a statistically significant decrease in total white blood cell (WBC) counts among exposed workers. The SNPs in WRN and TP53 remained significant after accounting for multiple comparisons. One or more SNPs in WRN had broad effects on WBC subtypes, with significantly decreased granulocyte, total lymphocyte, CD4(+)-T cell, CD8(+)-T cell and monocyte counts. Haplotypes of WRN were associated with decreased WBC counts among benzene-exposed subjects. Likewise, subjects with TP53 Ex4 +119 C > G variant had reduced granulocyte, CD4(+)-T cell and B cell counts. The effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes. These results suggest that genetic polymorphisms in WRN, TP53 and BRCA2 that maintain genomic stability impact benzene-induced hematotoxicity.
Carcinogenesis 2006 Oct
PMID:Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. 1672 35

Lactoferrin, an evolutionarily old protein of the transferrin family, is among the proteins constituting the system of innate immunity; its action, however, also extends to the regulation of acquired immunity and other immunological phenomena. The actions of LF, confirmed in numerous in vitro and in vivo models, include participation in iron homeostasis, immunoregulatory properties, anti-inflammatory, anti-tumor, and analgesic actions, regulation of bone metabolism, participation in embryonic development, reproductive functions, and others. LF plays an important role in the normal development of a newborn. The anti-tumor properties of LF were discovered about a decade ago and have been confirmed in many laboratory, preclinical, and clinical studies. The immunomodulatory properties of LF play a major role in its anti-tumor actions. Such actions of LF appeared particularly effective in cancer patients with impaired immunity. The growth of tumors is facilitated by low expressions of MHC and co-stimulatory antigens on tumor cells and the induction of suppressor cells and other inhibitory products by tumors. Enhancement of an anti-tumor immunological response may, therefore, restrict tumor growth. Studies showed that LF elevates the number and increases the activity of T and B lymphocytes and NK cells, stimulates the release of a number of cytokines (IL-1, -6, -8, -18, IFN-gamma, TNF alpha), increases phagocytic activity and cytotoxicity of monocytes/macrophages, accelerates the maturation of T and B cells, and elevates the expression of several types of cellular receptors, such as CD4, zeta chain of the CD3 complex, LFA-1, CD11, ICAM-1, and selectin P. Apart from its immunomodulatory properties, LF exhibits direct anti-tumor actions, such as lytic, pro-apoptotic, anti-proliferative, anti-angiogenic, anti-oxidant activity and the chelation of iron ions. LF also possesses chemo-preventive properties, regulates the activity of phase I and II enzymes participating in the activation and detoxification of carcinogens, and regulates the composition of the intestinal microflora. In this way it prevents the generation of tumors and their development at early stages of carcinogenesis.
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PMID:[Antitumor and chemopreventive activity of lactoferrin]. 1688 6

Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme activity have shown chemopreventive activity in carcinogen-induced and transgenic rodent tumor models and clinically for colon cancer. However, the mechanism(s) by which COX-2 inhibitors reduce carcinogenesis remains controversial. We report herein that administration of the selective COX-2 inhibitor, celecoxib, significantly reduces the number of Gr1(+)CD11b(+) immature myeloid suppressor cells (IMSCs) during chemoprevention of 1,2-dimethylhydrazine diHCl-(1,2-DMH-) induction of large intestinal tumors in Swiss mice. Celecoxib administration also increased splenic lymphatic number and tumor infiltration by lymphocytes. The 1,2-DMH induction of large intestinal tumors was associated with a four-fold increase in IMSCs, and a decrease in splenic T cell number and function. Concordant with the changes in the IMSC frequency, messenger ribonucleic acid (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) were increased in the spleen of the tumor-bearing mice and normalized by celecoxib administration. In addition to delaying tumor induction, reducing tumor number, and increasing lymphocyte infiltration of tumors, celecoxib therapy reversed CD4(+) T cell loss, decreased IMSC numbers and increased mRNA levels of NOS-2 and Arg in the spleen. In summary, our results suggest that celecoxib chemoprevention of autochthonous intestinal tumors can regulate IMSCs and CD4(+) T cell numbers.
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PMID:Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. 1717 80

The aim of this study is to investigate whether an active immunoprophylactic approach combining specific antigens and adjuvant stimuli would be able to inhibit prostate carcinogenesis in transgenic TRAMP mice. A vaccine consisting of allogeneic large T antigen (TAg)-positive SV40-transformed cells combined with systemic recombinant IL-12 was administered to TRAMP mice, starting from when they were still tumor-free at 5-6 weeks of age. The combined vaccine significantly inhibited prostate carcinogenesis, giving a more than doubled median latency time of prostatic tumors (53 weeks in comparison to 26 weeks in control mice). Vaccination with cells alone or IL-12 treatment alone was poorly effective (median latency of 30 and 39 weeks, respectively). The combined vaccine induced a very high CD4 response biased toward the Th1 pathway, with the induction of a humoral response that included TAg-specific antibodies. Therefore, such active immunoprophylactic approach based on the combination of allogeneic SV40 TAg-positive cells and systemic administration of recombinant IL-12 significantly delayed autochthonous urogenital carcinogenesis driven by SV40 TAg in TRAMP mice.
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PMID:Inhibition of prostate carcinogenesis by combined active immunoprophylaxis. 1729 Mar 95

There is a longstanding but poorly understood epidemiologic link between inflammation and cancer. Consistent with this, we previously showed that alphabeta T cell deficiency can increase resistance to chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate. This provoked the hypothesis that alphabeta T cell deficiency removed T regulatory cells that limit the anti-tumor response or removed a specific tumor-promoting (T-pro) T cell population. Here we provide evidence for the latter, identifying a novel CD8(+) subset that is a candidate for T-pro cells. We demonstrate that CD8 cell-deficient mice show substantially less tumor incidence and progression to carcinoma, whereas susceptibility is restored by CD8(+) cell reconstitution. To characterize the putative T-pro cells, tumor-infiltrating lymphocytes were isolated from normal and CD4(-/-) mice, revealing an activated population of T cell receptor alphabeta(+)CD8(+)CD44(+)CD62L(-) cells expressing the inflammatory mediators IFNgamma, TNFalpha, and cyclooxygenase-2, but deficient in perforin, relative to recirculating cells of equivalent phenotype. This novel population of CD8(+) T cells has intriguing similarities with other lymphocytes that have been associated with tissue growth and invasiveness and has implications for inflammation-associated carcinogenesis, models of cancer immunosurveillance, and immunotherapeutic strategies.
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PMID:Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis. 1741 37

Chronic inflammation of mucosal surfaces renders them increasingly susceptible to epithelial cancers both in humans and mice. We have previously shown that anti-inflammatory CD4(+)CD45RB(lo)CD25(+) regulatory (Treg or T(R)) lymphocytes down-regulate inflammation and block development of bacteria-triggered colitis and colorectal cancer (CRC) in 129/SvEv Rag2-/- mice. Interestingly, T(R) cells collected from Interleukin (IL)-10-deficient cell donors not only failed to suppress carcinogenesis but instead promoted invasive mucinous colonic carcinoma with a strong gender bias expressing in male mice. We found we show that peritoneal invasion in this model is dependent on pleiotropic cytokine IL-6. Mucinous carcinoma arose rapidly and consistently after treatment with IL10-/- T(R) cells, which were found to express Foxp3+ and localize throughout tumor tissue. Carcinogenesis was rapidly reversible with transfer of wild type IL10-competent T(R) cells. Likewise, treatment with IL10-Ig fusion protein was sufficient to revert the lesions histologically, and restore inflammatory cytokine and oncogene expression to base line levels. These studies indicate an essential role for IL 6 in this CRC phenotype. Furthermore, immune-competent T(R) cells were important not only for preventing pathology but also for constructive remodeling of bowel following tumorigenic microbial insults. These data provide insights into etiopathogenesis of inflammation-associated epithelial invasion and maintenance of epithelial homeostasis.
Carcinogenesis 2007 Dec
PMID:Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma. 1772 75

Cyclooxygenase 2 (COX-2) overexpression and production of prostaglandin E(2) (PGE(2)) by head and neck squamous cell carcinomas (HNSCC) induce type 1 regulatory T (Tr1) cells and contribute to carcinogenesis by creating a tolerogenic milieu. To test this hypothesis, CD4(+)CD25(-) T cells obtained from the peripheral blood of 10 normal donors were cocultured with autologous dendritic cells, irradiated HNSCC cells and cytokines, interleukin 2 (IL-2), IL-10, and IL-15. HNSCC cells were either COX-2 negative, constitutively expressed COX-2, were transfected with COX-2, or had COX-2 expression knocked down by small interfering RNA. Other modifications included coculture plus or minus the COX-inhibitor, Diclofenac, or synthetic PGE(2) in the absence of HNSCC. Lymphocytes proliferating in 10-day cocultures were phenotyped by flow cytometry, studied for cytokine production by ELISA and for suppressor function in CFSE inhibition assays plus or minus anti-IL-10 or anti-transforming growth factor-beta(1) (TGF-beta(1)) monoclonal antibodies (mAb). COX-2(+) HNSCC or exogenous PGE(2) induced outgrowth of Tr1 cells with the CD3(+)CD4(+)CD25(-)IL2Rbeta(+)IL2Rgamma(+)FoxP3(+)CTLA-4(+)IL-10(+)TGF-beta(1)(+)IL-4(-) phenotype and high suppressor functions (range, 46-68%). Small interfering RNA knockout of COX-2 gene in HNSCC led to outgrowth of lymphocytes with decreased IL2Rgamma (P = 0.0001), FoxP3 (P = 0.05), and IL-10 (P = 0.035) expression and low suppressor activity (range, 26-34%). Whereas COX-2(+) cocultures contained IL-10 and TGF-beta(1) (medians, 615 and 824 pg/mL), cytokine levels were decreased (P < 0.0001) in COX-2(-) cocultures. Inhibition of COX-2 enzymatic activity in HNSCC abrogated outgrowth of Tr1 cells. Neutralizing mAbs to IL-10 and/or TGF-beta(1) abolished Tr1-mediated suppression. COX-2 overexpression in HNSCC plays a major role in the induction of Tr1 cells in the tumor microenvironment.
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PMID:Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. 1787 28


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