linoleic-acid and Adenoma

Topics: Adenoma; Animals; Anticarcinogenic Agents; Arachidonic Acid; Biomarkers, Tumor; Colorectal Neoplasms; CpG Islands; Cyclooxygenase 2; Dietary Supplements; Dinoprostone; DNA Methylation; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Linoleic Acid; Membrane Proteins; Meta-Analysis as Topic; Odds Ratio; Prostaglandin-Endoperoxide Synthases; Proteins; Randomized Controlled Trials as Topic; Risk Assessment; Selenium Compounds; Selenoproteins

Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time.. This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Colorectal Neoplasms; Humans; Linoleic Acid; Metabolomics

Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta,17beta-diol disulfate 1; 5-alpha-androstan-3beta,17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E,Z or Z,E); cyclo (-leu-pro); dihomo-linoleate (20:2n6); and palmitoleate (16:1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR 4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma.

Topics: Adenoma; Aged; Alcohol Drinking; Alcoholic Beverages; Androstane-3,17-diol; Bilirubin; Biomarkers; Case-Control Studies; Colorectal Neoplasms; Dipeptides; Ethanol; Fatty Acids, Monounsaturated; Female; Glucuronates; Humans; Linoleic Acid; Male; Middle Aged; Odds Ratio; Palmitic Acids; Peptides, Cyclic

Epidemiological studies have provided inconsistent data about the role of dietary fatty acids in colorectal cancer, and few studies have addressed their role in colorectal adenoma. The aim of the study was to assess the risk of overall adenoma recurrence associated with dietary consumption of total fat, subtypes of fat, and specific fatty acids (oleic acid, linoleic acid, alpha-linolenic acid). The study sample was composed of 523 patients with confirmed adenomas at the index colonoscopy, 35 to 75 yr old, who completed the European fiber-calcium intervention trial and had an initial dietary assessment using a qualitative and quantitative food questionnaire. The overall 3-yr recurrence rate was 22.6% (118 out of 523 patients). There were no significant associations between overall adenoma recurrence and either total fat, subtypes of fat, or specific fatty acids. However, polyunsaturated fatty acids and linoleic acid were both moderately but significantly associated with distal and multiple recurrence. No significant associations were observed with recurrence of proximal or advanced adenomas. Our findings do not support the hypothesis of strong associations between dietary fatty acids and recurrence of colorectal adenomas. The hypothesis of a differential role of specific fatty acids according to colorectal subsites deserves further investigation.

Topics: Adenoma; Adult; Aged; Colorectal Neoplasms; Diet; Dietary Fats; Europe; Fatty Acids; Fatty Acids, Unsaturated; Female; Humans; Linoleic Acid; Male; Middle Aged; Neoplasm Recurrence, Local; Odds Ratio; Risk Factors; Surveys and Questionnaires

Two different pathways of linoleic acid (LA) metabolism have opposite effects on the development of colonic cancer: a protumoral prostaglandin cascade metabolized by cyclooxygenase (COX)-2, and an antitumoral peroxisome proliferator-activated receptor (PPAR)-gamma ligands metabolized by 15-lipooxygenase (LOX)-1. The aim was to examine the switching of the two LA metabolic pathways in colonic adenomas and carcinomas.. The expression of 15LOX-1 mRNA and COX-2 protein was examined in 54 adenomas, 21 pTis carcinoma-in-adenoma lesions and 36 pT3/p Stage II carcinomas of the colon by in-situ hybridization and immunohistochemistry, respectively.. 15LOX-1 expression was found in 89% (48 of 54) of adenomas, 43% (nine of 21) of adenomas and 10% (two of 21) of carcinomas in carcinoma-in-adenoma lesions, but not in pT3 carcinomas (P < 0.0001). In contrast, COX-2 production was found in 11% (six of 54) of adenomas, 52% (11 of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Concurrence of 15LOX-1 down-regulation and COX-2 up-regulation was found in 6% (three of 54) of adenomas, 33% (seven of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001).. These results suggest that switching of LA metabolism by reversal of the expression of 15LOX-1 and COX-2 is associated with acquisition of malignant potential in colonic neoplasia.

Topics: Adenoma; Aged; Aged, 80 and over; Arachidonate 15-Lipoxygenase; Carcinoma; Colonic Neoplasms; Cyclooxygenase 2; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Linoleic Acid; Male; Middle Aged; Neoplasm Staging; RNA, Messenger

Topics: Adenoma; Animals; Anticarcinogenic Agents; Colonic Neoplasms; Disease Models, Animal; Drinking; Fatty Acids; Genes, APC; Linoleic Acid; Male; Mice; Mice, Mutant Strains; Random Allocation

The influence of dietary fats on azoxymethane-induced colorectal carcinogenesis and erythrocyte, adipose, colon mucosa and tumour tissue fatty acids was investigated in 228 Wistar rats. The two main diets compared were beef suet rich in saturated fatty acids and corn oil rich in a linoleic acid, an N-6 polyunsaturated fatty acid. The animals were placed in one of four dietary groups: A = 5% saturated fat, B = 20% saturated fat, C = 5% N-6 fat and D = 20% N-6 fat. There was no difference in the number of adenomas between any of the dietary groups. The mean (+/- SEM) carcinoma yield per rat was A = 0.93 +/- 0.28, B = 1.93 +/- 0.50, C = 0.70 +/- 0.07, D = 0.13 +/- 0.04; the tumour yields in rats fed the saturated fat diets were significantly different from each other and from those fed the N-6 fat diets. The fatty acid profiles in all tissues were dependent upon the type and level of dietary fat and the tissue type. Arachidonate was higher in tumours compared to normal mucosa. Significant correlations were found between adipose linoleate (reflecting dietary intake) and tumour oleate and tumour arachidonate but not with the colorectal mucosa of control animals. This is the first in vivo study to show reduced colorectal carcinogenesis by N-6 polyunsaturated fatty acids.

Topics: Adenoma; Adipose Tissue; Animals; Arachidonic Acid; Arachidonic Acids; Azoxymethane; Carcinoma; Cell Membrane; Colorectal Neoplasms; Fats, Unsaturated; Fatty Acids; Intestinal Mucosa; Linoleic Acid; Linoleic Acids; Male; Oleic Acid; Oleic Acids; Palmitic Acid; Palmitic Acids; Rats; Rats, Inbred Strains; Stearic Acids; Weight Gain