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

Fatty acid composition of dietary fat plays a vital role in colon tumor development in animal models. Fats containing omega-6 fatty acids (e.g., corn oil) enhanced and omega-3 fatty acids (e.g., flaxseed oil) reduced chemically induced colon tumor development in rats. Lignans have also been shown to prevent colon tumor development in experimental animals. The objective of this investigation is to study the effects of dietary flaxseed meal, a source of both omega-3 fatty acid and lignans, on colon tumor development and compare them with the effects of dietary corn meal. Male Fischer rats, two groups of 24 each, were assigned to the AIN-93M diet supplemented with either 15% corn meal or 15% flaxseed meal, respectively. Carcinogenesis was initiated with subcutaneous injections of azoxymethane (15 mg/kg) once a week for 3 consecutive wk. After 35 wk of initiation, rats were anesthetized with ether. Blood was collected by cardiac puncture, and rats were sacrificed. The gastrointestinal tract was isolated. The site, size, and number of tumors were recorded. The fatty acid analysis of the collected serum and colon samples was performed. Expression of cyclooxygenase (COX)-1 and COX-2 was performed by Western blot method. Lignan levels in serum and colon samples were assayed. Colon tumor incidence, multiplicity, and size were found to be 82.6% and 29.4%; 1.3 and 0.3; and 44.4 and 5.3 mm(2) in corn and flaxseed meal groups, respectively. Colon and serum samples of the corn meal group showed higher levels of omega-6 fatty acid levels whereas the flaxseed meal group exhibited higher levels of omega-3 fatty acids. COX-1 and COX-2 expression in the flaxseed group was significantly lower (P < 0.05) as compared to the corn group. Dietary flaxseed meal containing high levels of omega-3 fatty acids and lignans is effective in preventing colon tumor development when compared with dietary corn meal possibly by increasing omega-3 fatty acid levels and decreasing COX-1 and COX-2 levels.
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PMID:Chemopreventive effects of dietary flaxseed on colon tumor development. 1689 66

Colon carcinogenesis is a multistep process that involves deletions, mutations, and changes in expression of genes that regulate growth, differentiation, and apoptosis. Hyperproliferation can initiate dysplastic growth, resulting in accumulation of genetic defects and progression of colon cancer. Although genetic instability, because of inheritance of specific genetic defects, plays a dominant role in familial cancers, in the majority of sporadic cancers hyperproliferation is likely to play a permissive role in initiation and progression of the disease. Thus factors that regulate growth, differentiation, and apoptosis are likely to play an important role in colon carcinogenesis. Autocrine gastrins, insulin-like growth factor-II, transforming growth factor-alpha, and endocrine gastrins have been implicated in the tumorigenic potential of colon cancer cells. In this article we focus on the role of endocrine and autocrine gastrins in colon cancer and review recent advances that suggest a role of processing intermediates of gastrin in colon carcinogenesis.
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PMID:Role of autocrine and endocrine gastrin-like peptides in colonic carcinogenesis. 1702 20

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 micromol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.
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PMID:Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. 1705 95

Mouse models for colon cancer that harbor a germ line mutation in the tumor suppressor gene Adenomatous polyposis coli (Apc) exhibit a primary genetic defect that predisposes to a high incidence of adenomatous polyps in the small intestine rather than in the colon. Colon cell culture models expressing quantifiable markers for carcinogenic risk may represent an alternative approach to reduce, refine or replace long-term animal experimentation. The newly developed colon epithelial cell lines 1638N COL-Cl(1) (clonal derivative of the parental Apc mutant cell line 1638N COL) and 1638N COL-Pr(1) (tumor derivative of the clone), established from an Apc1638N [+/-] mutant mouse, exhibit aberrant cell cycle progression, downregulated apoptosis, enhanced carcinogenic risk and tumor formation, indicating that aberrantly proliferative preneoplastic1638N COL-Cl(1) cells exhibit a quantifiable risk for carcinogenesis. Treatment of these preneoplastic Apc mutant cells with a combination of celecoxib and 5-fluorouracil at clinically achievable low concentrations produced a 2.1 fold to 5.5 fold higher efficacy for cytostatic growth arrest and a 40.2% to 52.4% higher efficacy for inhibition of carcinogenic risk, relative to that obtained by these agents used individually. Thus, a low dose combination of mechanistically distinct agents resulted in enhanced efficacy. These data validate a novel cell culture model and a rapid mechanism-based approach to prioritize efficacious drug combinations for animal studies and clinical trials on cancer prevention and, thereby, support the 3R concept by refining and/or reducing the use of animals in biomedical research relevant to prevention/therapy of colon cancer.
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PMID:Cell culture model for colon cancer prevention and therapy: an alternative approach to animal experimentation. 1736 17

The bitter acids of hops (Humulus lupulus L.) mainly consist of humulones or alpha-acids and lupulones or beta-acids. We aimed to evaluate the antiproliferative mechanisms of lupulones on a human metastatic colon carcinoma-derived cell line (SW620 cells) and to assess their chemopreventive effects in a model of colon carcinogenesis. SW620 cell growth was inhibited by 70% after a 48 h exposure to lupulones (40 microg/ml). Lupulones up-regulated the expression of Fas receptor (Fas) and Fas ligand (FasL) as well as TNF-related apoptosis inducing ligand (TRAIL)-R1 (DR4) and -R2 (DR5) receptor proteins, suggesting the involvement of Fas and TRAIL receptors-mediated pathways in lupulone-induced apoptosis. Lupulones also increased the mitochondrial membrane permeability. Colon carcinogenesis was initiated in Wistar rats by intra-peritoneal injections of azoxymethane (AOM), once a week for 2 weeks. One week after the last injection, rats received lupulones (0.001 or 0.005%) in drinking water, and AOM-control rats received the excipient. After 7 months of treatment, the colon of rats receiving 0.001 and 0.005% lupulones showed, respectively, a 30 and a 50% reduction (P < 0.05) of the number of preneoplastic lesions (aberrant crypt foci). In addition, we observed a drastic reduction (70-80%) of the total number of tumors in the colon of rats treated with lupulones when compared with the AOM control group. Lupulones induced apoptosis in SW620 colon-derived metastatic cells by activating both Fas and TRAIL death receptor signaling pathways, and antagonize at a low dose (4 mg/kg/day) colon cancer development. These observations suggest the use of lupulones for colon cancer chemoprevention trials.
Carcinogenesis 2007 Jul
PMID:Chemopreventive effects of lupulone, a hop {beta}-acid, on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis. 1743 26

Intake of linoleic acid (LA) increased etheno-DNA adducts induced by lipid peroxidation (LPO) in white blood cells (WBC) of female but not of male volunteers [J. Nair, C.E. Vaca, I. Velic, M. Mutanen, L.M. Valsta, H. Bartsch, High dietary omega-6 polyunsaturated fatty acids drastically increase the formation of etheno-DNA adducts in white blood cells of female subjects, Cancer Epidemiol. Biomarkers Prev. 6 (1997) 597-601]. Etheno-adducts were measured in rats gavaged with LA, oleic acid (OA) and saturated fatty acid rich coconut oil for 30 days. DNA from organs and total WBC was analyzed for 1, N(6)-ethenodeoxyadenosine (varepsilondA) and 3, N(4)-ethenodeoxycytidine (varepsilondC) by immunoaffinity/(32)P-postlabeling. Colon was the most affected target with LA-treatment, where etheno-adducts were significantly elevated in both sexes. In WBC both adducts were elevated only in LA-treated females. Unexpectedly, OA treatment enhanced etheno-adduct levels in prostate 3-9 fold. Our results in rodents confirm the gender-specific increase of etheno-adducts in WBC-DNA, likely due to LPO induced by redox-cycling of 4-hydroxyestradiol. Colon was a target for LPO-derived DNA-adducts in both LA-treated male and female rats, supporting their role in omega-6 PUFA induced colon carcinogenesis.
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PMID:Etheno-DNA adduct formation in rats gavaged with linoleic acid, oleic acid and coconut oil is organ- and gender specific. 1752 82

The present study evaluated the inhibitory effects of zinc on colonic antioxidant defense system and histoarchitecture during 1,2 dimethylhydrazine (DMH) induced colon carcinogenesis in male Spraque Dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH + zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 8 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/l in drinking water, ad libitum for the entire duration of the study. Increased lipid peroxidation was accompanied by a decrease in reduced glutathione (GSH), glutathione reductase (GR), glutathione-s-transferase (GST), superoxide dismutase (SOD), and catalase. Administration of zinc to DMH treated rats significantly decreased the lipid peroxidation levels with simultaneous enhancement of GSH, GR, GST, SOD, and Catalase. Histopathological studies from DMH treated rats revealed disorganization of colonic histoarchitecture. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of abnormality. Energy Dispersive X-Ray Fluorescence (EDXRF) studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplementation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a beneficial effect during the initiation of key events leading to the development of experimentally induced carcinogenesis.
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PMID:Zinc mediated normalization of histoarchitecture and antioxidant status offers protection against initiation of experimental carcinogenesis. 1753 Jan 92

The present study was performed to evaluate the efficacy of zinc treatment on colonic antioxidant defense system and histoarchitecture in 1,2-dimethylhydrazine- (DMH) induced colon carcinogenesis in male Sprague-Dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH+zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 16 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum for the entire duration of the study. Increased tumor incidence, tumor size and number of aberrant crypt foci (ACF) were accompanied by a decrease in lipid peroxidation, glutathione-S-transferase, superoxide dismutase (SOD) and catalase. On the contrary, significantly increased levels of reduced glutathione (GSH) and glutathione reductase (GR) were observed in DMH treated rats. Administration of zinc to DMH treated rats significantly decreased the tumor incidence, tumor size and aberrant crypt foci number with simultaneous enhancement of lipid peroxidation, SOD, catalase and glutathione-S-transferase. Further, the levels of GSH and GR were also decreased following zinc supplementation to DMH treated rats. Well-differentiated signs of dysplasia were evident in colonic tissue sections by DMH administration alone. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of neoplasia. EDXRF studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplementation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats induced by DMH.
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PMID:Chemopreventive potential of zinc in experimentally induced colon carcinogenesis. 1759 May 43

Colon cancers have been shown to develop after accumulation of multiple genetic and epigenetic alterations with changes in global gene expression profiles, contributing to the establishment of widely diverse phenotypes. Transcriptional and posttranscriptional regulation of gene expression by small RNA species, such as the small interfering RNA and microRNA and the RNA-induced silencing complex (RISC), is currently drawing major interest with regard to cancer development. SND1, also called Tudor-SN and p100 and recently reported to be a component of RISC, is among the list of highly expressed genes in human colon cancers. In the present study, we showed remarkable up-regulation of SND1 mRNA in human colon cancer tissues, even in early-stage lesions, and also in colon cancer cell lines. When mouse Snd1 was stably overexpressed in IEC6 rat intestinal epithelial cells, contact inhibition was lost and cell growth was promoted, even after the cells became confluent. Intriguingly, IEC6 cells with high levels of Snd1 also showed an altered distribution of E-cadherin from the cell membrane to the cytoplasm, suggesting loss of cellular polarity. Furthermore, the adenomatous polyposis coli (Apc) protein was coincidentally down-regulated, with no significant changes in the Apc mRNA level. Immunohistochemical analysis using chemically induced colonic lesions developed in rats revealed overexpression of Snd1 not only in colon cancers but also in aberrant crypt foci, putative precancerous lesions of the colon. Up-regulation of SND1 may thus occur at a very early stage in colon carcinogenesis and contribute to the posttranscriptional regulation of key players in colon cancer development, including APC and beta-catenin.
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PMID:SND1, a component of RNA-induced silencing complex, is up-regulated in human colon cancers and implicated in early stage colon carcinogenesis. 1790 68

The poor efficacy of reference chemotherapy (fluorouracil -FU) in colon cancer has resulted in a constant search for agents which could augment the action of FU. Epidemiological data, such as the decreased risk of colorectal cancer among menopausal women receiving hormonal replacement therapy, indicate the role of oestrogen in the pathogenesis of this disease. The differences between normal and neoplastic colon cells in the expression of oestrogen receptor beta (ERbeta) could confirm this association. However, the direct influence of oestrogen or tamoxifen (SERM, selective oestrogen receptor modulator) on colon cancer growth has rarely been studied. The aim of the present study was to examine the direct effects of various concentrations of oestradiol and tamoxifen (10(-4) to 10(-12) M), applied alone or together with FU, on the growth of murine Colon 38 cancer in vitro as assessed by three colorimetric methods: Mosmann's method, incorporation of BrdU into cell nuclei and the TUNEL method. At high concentrations oestradiol and tamoxifen decreased the cancer growth in a dose- and time-dependent manner (the Mosmann and BrdU methods) and at some concentrations augmented the cytotoxic action of FU (Mosmann's method). Tamoxifen exerted a very early and potent inhibitory effect, inducing even total cancer growth inhibition at the concentration of 10(-4) M (the Mosmann and BrdU methods). All the substances studied at different concentrations and at different incubation time points increased the apoptosis of tumour cells (the TUNEL method). The results indicate that oestradiol and tamoxifen inhibit Colon 38 cancer growth and increase the cytotoxic effect of FU, which confirms the role of sex steroids in colon carcinogenesis and even suggests new therapeutic schemes.
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PMID:Oestradiol and tamoxifen inhibit murine Colon 38 cancer growth and increase the cytotoxic effect of fluorouracil. 1805 39


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