linoleic-acid and Colorectal-Neoplasms

Several associations between non-genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta-analyses of observational studies, meta-analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non-genetic biomarkers and CRC risk and meta-analyses of RCTs on supplementary micronutrients. We repeated the meta-analyses using random-effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy-two meta-analyses of observational studies and 18 MR studies on non-genetic biomarkers and six meta-analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta-analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non-genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment-insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types.

Topics: Arachidonic Acid; Biomarkers, Tumor; Colorectal Neoplasms; Helicobacter Infections; Helicobacter pylori; Humans; Insulin Resistance; Linoleic Acid; Mendelian Randomization Analysis; Meta-Analysis as Topic; Micronutrients; Observational Studies as Topic; Oleic Acid; Papillomavirus Infections; Randomized Controlled Trials as Topic; Risk; Vitamin D

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a lower omega-6/omega-3 ratio), exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries.

Topics: alpha-Linolenic Acid; Biological Evolution; Blood Platelets; Cardiovascular Diseases; Cell Proliferation; Chronic Disease; Colorectal Neoplasms; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Humans; Linoleic Acid; Models, Biological; Platelet Aggregation; Risk

This study reviews epidemiological works having studied the associations of dietary fatty acids, especially of n-6 or n-3 polyunsaturated fatty acids (PUFA), with the risks of colorectal and prostate cancers.. The epidemiological studies reviewed were those having tested the association of colorectal and prostate cancer risk with the dietary intake or the blood or adipose tissue levels of fatty acids, especially of n-6 and n-3 PUFA, and with the dietary intake of fish and seafood.. Most studies based on a dietary questionnaire did not find any association of the risk of colorectal cancer with the consumption of either total fatty acids or any particular fatty acid, after adjustment for total energy intake had been made. A few studies suggest that trans fatty acid consumption could increase colorectal cancer risk. Most studies based either on a dietary questionnaire or on biomarkers, did not find any association of total, saturated or monounsaturated fatty acid, as well as of linoleic or arachidonic acids, with prostate cancer risk, after adjustment for total energy intake. Most studies failed to find an association of prostate cancer risk with fish or long-chain n-3 PUFA intake, but recent cohort studies did find an inverse association of fish consumption with the risk of the latest stages of prostate cancer. In contrast, alpha-linolenic acid intake was associated with an increase of prostate cancer risk in a majority of epidemiological studies, but other studies did not find this association. This latter point might be of concern, and needs to be clarified by other results, especially those of ongoing prospective studies.

Topics: alpha-Linolenic Acid; Animals; Colorectal Neoplasms; Dietary Fats; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fishes; Humans; Linoleic Acid; Male; Prostatic Neoplasms; Trans Fatty Acids

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

Replacement of saturated fat by the major dietary polyunsaturated fat linoleic acid reduces blood cholesterol concentrations and the risk of coronary artery disease. However, there is concern that long-term consumption of large amounts of linoleic acid might increase cancer risk. We reviewed the epidemiologic and experimental literature on linoleic acid intake and cancer risk and performed additional meta-analyses of risk estimates from case-control and prospective cohort studies. None of the combined estimates from within-population studies indicated a significantly increased risk of cancer with high compared with low intakes of linoleic acid or polyunsaturated fat. For case-control studies, the combined relative risks were 0.84 (95% CI: 0.71, 1.00) for breast, 0.92 (95% CI: 0.85, 1.08) for colorectal, and 1.27 (95% CI: 0.97, 1.66) for prostate cancer. For prospective cohort studies, combined relative risks were 1.05 (95% CI: 0.83, 1.34) for breast, 0.92 (95% CI: 0.70, 1.22) for colon, and 0.83 (95% CI: 0.56, 1.24) for prostate cancer. Ecologic comparisons of populations showed positive associations between cancer rates and per capita use of animal or saturated fat, but less so with per capita use of vegetable oil or polyunsaturated fat. Controlled studies of coronary artery disease in men did not, except for 1 study, show an increased cancer incidence after consumption of diets with a very high linoleic acid content for several years. Animal experiments indicated that a minimum amount of linoleic acid is required to promote growth of artificially induced tumors in rodents; but above this threshold, linoleic acid did not appear to have a specific tumor-promoting effect. Although current evidence cannot exclude a small increase in risk, it seems unlikely that a high intake of linoleic acid substantially raises the risks of breast, colorectal, or prostate cancer in humans.

Topics: Animals; Breast Neoplasms; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Female; Humans; Linoleic Acid; Male; Neoplasms; Prospective Studies; Prostatic Neoplasms; Risk Factors

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

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are functionally the most important omega-3 polyunsaturated fatty acids (PUFAs). Oral supply of these fatty acids increases their levels in plasma and cell membranes, often at the expense of the omega-6 PUFAs arachidonic acid (ARA) and linoleic acid. This results in an altered pattern of lipid mediator production to one which is less pro-inflammatory. We investigated whether short term intravenous supply of omega-3 PUFAs could change the levels of EPA, DHA, ARA and linoleic acid in plasma and erythrocytes in patients with hepatic colorectal metastases.. Twenty patients were randomised to receive a 72 hour infusion of total parenteral nutrition with (treatment group) or without (control group) omega-3 PUFAs. EPA, DHA, ARA and linoleic acid were measured in plasma phosphatidylcholine (PC) and erythrocytes at several times points up to the end of infusion and 5 to 12 days (mean 9 days) after stopping the infusion.. The treatment group showed increases in plasma PC EPA and DHA and erythrocyte EPA and decreases in plasma PC and erythrocyte linoleic acid, with effects most evident late in the infusion period. Plasma PC and erythrocyte EPA and linoleic acid all returned to baseline levels after the 5-12 day washout. Plasma PC DHA remained elevated above baseline after washout.. Intravenous supply of omega-3 PUFAs results in a rapid increase of EPA and DHA in plasma PC and of EPA in erythrocytes. These findings suggest that infusion of omega-3 PUFAs could be used to induce a rapid effect especially in targeting inflammation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arachidonic Acid; Child; Colorectal Neoplasms; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Inflammation; Linoleic Acid; Liver Neoplasms; Male; Middle Aged

The incidence of colorectal cancer is rapidly increasing in Japan. This trend has been suggested to be caused by an increasing fat intake as a result of the Westernized diet among Japanese. We investigated whether dietary instruction optimizing the fat energy ratio suppresses the recurrence of colorectal tumors. The subjects, 373 men and women, were the participants in a randomized clinical trial of colorectal cancer prophylaxis. At entry, each participant completed a 3-consecutive-day food record on which dietary instruction was given to restrict fat energy ratio to 18-22%. Data obtained before and after the intervention were examined by cohort analysis. The primary endpoint was the presence or absence of colorectal tumor(s) at colonoscopy after 4 yr. Unexpectedly, the recurrence of tumor increased as the subjects reduced their fat intake. The lowest tumor recurrence among the men was observed in the group with 23.8-26.4% fat energy ratio after the intervention. Furthermore, in men, the risk of tumors decreased significantly as the intake of linoleic acids per body weight increased. For women, similar trends were observed. These results suggest that extreme fat restriction is highly likely to promote the recurrence of colorectal tumors, which may be partly attributable to linoleic acid deficiency.

Topics: Adult; Age Factors; Aged; Colonoscopy; Colorectal Neoplasms; Diet Records; Diet, Fat-Restricted; Dietary Fiber; Energy Intake; Female; Humans; Lacticaseibacillus casei; Linoleic Acid; Male; Middle Aged; Neoplasm Recurrence, Local; Odds Ratio; Probiotics; Sex Factors

Topics: Adenomatous Polyposis Coli; Anticarcinogenic Agents; Arachidonic Acid; Cell Division; Colon; Colorectal Neoplasms; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fish Oils; Food, Fortified; Humans; Intestinal Mucosa; Linoleic Acid; Mitotic Index; Rectum

Linoleic acid (LA) has been shown to cause inflammation and promote development of colorectal cancer (CRC). Moreover, many literatures show that LA is associated with cancer metastasis. Metastatic cancer cells have high stemness, suggesting that LA might affect the stemness of cancer cells. In this study, we examined the effect of LA on the hedgehog system, which affects cancer stemness. In CT26 cells, LA treatment induced the expression of sonic hedgehog

Topics: Animals; Colorectal Neoplasms; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Linoleic Acid; Liver Neoplasms; Mice; Nuclear Proteins; Transcription Factors; Zinc Finger Protein Gli2

Obesity is one of the risk factors concerns of colorectal cancer (CRC), the most common type of gastrointestinal cancer, due to the changing lifestyle and especially diet. There are various molecular pathways associated with obesity and the risk of CRC incidence, such as insulin resistance or elevated plasma free fatty acids, which alter the signaling pathways of intestinal epithelial cells. The aim of this study was to better understand the significance of unsaturated fatty acid biosynthesis on pathogenesis of colon cancer in obese. Based on GSE20931 dataset, obese individuals affected by CRC had higher increased gene expression than non-obese individuals. The analysis showed that in obese individuals, the 16 signaling pathway genes were activated and increased (FDR <0.05) significantly. The biosynthetic pathway of unsaturated fatty acids showed a cross-talk with the arachidonic acid metabolism pathway and the PPAR signaling pathway is influenced and regulated via these pathways. The biosynthetic pathway of unsaturated fatty acids consisting of 22 genes, were analyzed using GEO data and revealed that 4 genes (HSD17B12, TECR, FADS2, ELOVL5) from this pathway were significantly increased (FDR <0.05). These data were validated based on TCGA data (Adj.p.value <0.001). The expression level of candidate genes in HT-29 cells decreased significantly (P.value <0.01), and PPARγ expression increased under linoleic acid treatment (200 μM) compared to control cells. Moreover, in presence of linoleic acid treatment, migration, colony formation, and proliferation decreased (P.value <0.01) in presence of treatment. In summary, the Biosynthesis pathway of unsaturated fatty acids is an interesting and critical pathway in CRC.

Topics: Adipogenesis; Colorectal Neoplasms; Fatty Acids, Unsaturated; Humans; Insulin Resistance; Linoleic Acid; Obesity

The lungs and large intestine can co-regulate inflammation and immunity through the lung-gut axis, in which the transportation of the gut microbiota and metabolites is the most important communication channel. In our previous study, not only did the composition of the gut microbiota and metabolites related to inflammation change significantly during the transition from ulcerative colitis (UC) to colorectal cancer (CRC), but the lung tissues also showed corresponding inflammatory changes, which indicated that gastrointestinal diseases can lead to pulmonary diseases. In order to elucidate the mechanisms of this lung-gut axis, metabolites in bronchoalveolar lavage fluid (BALF) and lung tissues were detected using UHPLC-Q-TOF-MS/MS technology, while microbiome characterization was performed in BALF using 16S rDNA sequencing. The levels of pulmonary metabolites changed greatly during the development of UC to CRC. Among these changes, the concentrations of linoleic acid and 7-hydroxy-3-oxocholic acid gradually increased during the development of UC to CRC. In addition, the composition of the pulmonary microbiota also changed significantly, with an increase in the

Topics: Colitis, Ulcerative; Colorectal Neoplasms; DNA, Ribosomal; Humans; Inflammation; Linoleic Acid; Lung; Tandem Mass Spectrometry

Cancer dormancy is a state characterized by the quiescence of disseminated cancer cells, and tumor recurrence occurs when such cells re-proliferate after a long incubation period. These cancer cells tend to be treatment resistant and one of the barriers to successful therapeutic intervention. We have previously reported that long-term treatment of cancer cells with linoleic acid (LA) induces a dormancy-like phenotype. However, the mechanism underpinning this effect has not yet been clarified. Here, we investigate the mechanism of LA-induced quiescence in cancer cells. We first confirmed that long-term treatment of the mouse colorectal cancer cell line CT26 with LA induced quiescence. When these cells were inoculated subcutaneously into a syngeneic mouse and fed with an LA diet, the inoculated cancer cells maintained the quiescent state and exhibited markers of dormancy. LA-treated CT26 cells showed reduced oxidative phosphorylation, glycolysis, and energy production as well as reduced expression of the regulatory factors

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Glycolysis; Humans; Linoleic Acid; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; MicroRNAs; Mitochondria; Neoplasm Recurrence, Local; Oxidative Stress; Transcriptome; Up-Regulation

Colorectal cancer (CRC) is one of the most serious complications of ulcerative colitis (UC). Altered gut microbiota is implicated in the development of CRC and metabolic perturbations are often associated with changes in the gut microbiome composition. Given the links between gut microbiome and the metabolic profiles in the body, an approach involving ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) metabolomics and 16S rDNA sequencing technology was applied to trace the development UC into CRC in rats. The study identified 11 differential metabolites related to both UC and CRC, which mainly referred to the linoleic acid metabolism. Among these, linoleic acid and 12‑hydroxy‑8,10-octadecadienoic acid could serve as key biomarkers for the development of UC into CRC. Besides, a significant change was observed in the microflora structure during the development from UC to CRC; this mainly involved a gradual increase in Escherichia-Shigella and a gradual decrease in Lactobacillus. In addition, Pearson's correlation analysis revealed strong correlations between intestinal microflora-related metabolites and specific intestinal microflora, which indicated both of them can promote the transition of UC to CRC. The results of the present study provided positive support for the involvement of intestinal microflora and host metabolism in the pathophysiological mechanism that is responsible for the development of UC into CRC. This information can help understand the risk for CRC that accompanies a diagnosis of UC and also provide different means of targeting these differential metabolites and intestinal microbiota to avoid UC-induced CRC.

Topics: Animals; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Colorectal Neoplasms; Discriminant Analysis; Escherichia coli; Feces; Gastrointestinal Microbiome; Least-Squares Analysis; Linoleic Acid; Male; Metabolomics; Principal Component Analysis; Rats; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Shigella; Tandem Mass Spectrometry

The biomarker identification of cancer is benefit for early detection and less invasion. Polyunsaturated fatty acid (PUFA) metabolite as inflammatory mediators can affect progression and treatment of cancer. In this work, the serum was collected from colorectal cancer patients and healthy volunteers, and then we tested the change of serum PUFA metabolites in both of them by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Of the 158 PUFA and their metabolites, we found that abnormal change of 2, 3-dinor-8-iso-PGF2α, 19-HETE and 12-keto-LTB4 from arachidonic acid were observed in colorectal cancer patients. Meanwhile, 9-HODE and 13-HODE from linoleic acid were significant lower in colorectal cancer patients. Our data suggested that some PUFA metabolites might be used as a potential biomarker of colorectal cancer, which might provide assistance in clinical diagnosis and treatment.

Topics: Adult; Aged; Arachidonic Acid; Biomarkers; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Fatty Acids, Unsaturated; Female; Humans; Hydroxyeicosatetraenoic Acids; Linoleic Acid; Male; Middle Aged; Tandem Mass Spectrometry

Previous studies indicated that tomato is a rich source of phytochemicals that act on different tumours. In this research, the phytochemical composition of selected tomato varieties was assessed by GLC and UHPLC/HPLC-MS, as well as their anti-tumour activities on HT-29 colorectal cancer cells.. Significant differences were found among tomato varieties; lycopene was high in Racimo, phenolics in Pera, sterols in Cherry, and linoleic acid predominated in all varieties. The MTT and LDH assays showed significant time- and concentration-dependent inhibitory/cytotoxic effects of all tomato varieties on HT-29 cells. Furthermore, the joint addition of tomato carotenoids and olive oil to HT-29 cell cultures induced inhibitory effects significantly higher than those obtained from each of them acting separately, while no actions were exercised in CCD-18 normal cells.. Tomato fruits constitute a healthy source of phytochemicals, although differences exist among varieties. In vitro, all of them inhibit colorectal cancer cell proliferation with Racimo variety at the top, and exercising a selective action on cancer cells by considering the lack of effects on CCD-18 cells. Furthermore, synergy was observed between olive oil and tomato carotenoids in inhibiting HT-29 cancer cell proliferation; conversely, phenolics showed no significant effects and hindered carotenoids actions. © 2016 Society of Chemical Industry.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Carotenoids; Cell Proliferation; Colorectal Neoplasms; Dietary Fats, Unsaturated; Drug Synergism; Fruit; HT29 Cells; Humans; Linoleic Acid; Lycopene; Olive Oil; Phenols; Phytochemicals; Phytosterols; Phytotherapy; Plant Extracts; Solanum lycopersicum; Species Specificity

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

Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials.

Topics: Animals; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Colitis; Colorectal Neoplasms; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fruit; Gene Expression Regulation; Inflammation Mediators; Linoleic Acid; Linolenic Acids; Lipopolysaccharides; Macrophages; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Morus; Mucin-2; NF-kappa B; Nitric Oxide; Phosphorylation; Plant Extracts; Protein Transport; Signal Transduction

To investigate tissue fatty acid distribution in relation to the incidence of colorectal cancer prognosis, adjacent normal tissue and cancerous tissue from 35 samples of clinically incident colorectal cancer were obtained. Fatty acids were measured in the colorectal mucosa phospholipid fraction by gas chromatography mass spectrometry. Palmitoleic acid and oleic acid were significantly lower in colorectal cancerous tissue, ranging from 20% to 50% less than the adjacent normal tissue. The omega-6 (n-6) fatty acid family members (20:2, 20:3, 20:4 and 22:4) were higher by 1-3 fold in cancerous colorectal tissue. Contrary with the high level of n-6 fatty acids, about a 37% to 87% reduction in EPA and DHA was observed in colorectal cancerous tissue. A higher level of linoleic acid and arachidonic acid was detected in the C cancer stage than in the B cancer stage (p<0.05), but a lower level of oleic acid and docosahexenoic acid was detected in the C cancer stage (p<0.05). The fatty acid distribution of colorectal tissue is strongly linked to the incidence of colorectal cancer. This study also provides scientific basis for identifying novel biomarkers for the diagnosis and treatment of cancer.

Topics: Aged; Arachidonic Acid; Colon; Colorectal Neoplasms; Dietary Fats; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Gas Chromatography-Mass Spectrometry; Humans; Intestinal Mucosa; Linoleic Acid; Male; Middle Aged; Prognosis; Rectum

Topics: Caspases; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Inhibitor of Apoptosis Proteins; Linoleic Acid; Mitochondria; Mitochondrial Membranes; Survivin

Advanced glycation end products (AGE) and the receptor for advanced glycation end products (RAGE) are closely associated with colorectal cancer progression. The association between RAGE and AGE in colon carcinogenesis needs to be clarified.. Levels of RAGE and AGE were examined in azoxymethane (AOM)-injected Fischer 344 rats fed a control diet (Group C), a 15 % linoleic acid (LA) diet (Group L), a control diet with 10 % glucose drink (Group G), and a 15 % LA diet with 10 % glucose drink (Group L + G). Group L + G showed the most pronounced increase of body weight, blood sugar, and serum insulin.. The rats in Group L + G showed the most pronounced multiplicity of aberrant crypt foci (ACF) and carcinomas with increased mucosal RAGE and AGE. IEC6 rat intestinal epithelial cells treated with AGE showed increased RAGE expression, which was inhibited by treatment with metformin or losartan. In the AOM-injected rat colon cancer model, the levels of RAGE and AGE, and the multiplicity of ACF and carcinomas, in Group L + G rats were suppressed by treatment with metformin or losartan.. These results suggest that AGE-RAGE induced by high-LA and high-glucose diets substantially enhances colon cancer development; thus, suppression of AGE-RAGE could be a potential target for colon cancer chemoprevention.

Topics: Animals; Azoxymethane; Body Weight; Carcinogens; Cell Culture Techniques; Colon; Colorectal Neoplasms; Diet; Enzyme-Linked Immunosorbent Assay; Glucose; Glycation End Products, Advanced; Immunoblotting; Immunohistochemistry; Intestinal Mucosa; Linoleic Acid; Male; Rats; Rats, Inbred F344; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Some polyunsaturated fatty acids (PUFAs), if not all, have been shown to have tumoricidal action, but their exact mechanism(s) of action is not clear. In the present study, we observed that n-6 PUFA linoleic acid (LA) inhibited tumor cell growth at high concentrations (above 300 μM); while low concentrations (100-200 μM) promoted proliferation. Analysis of cell mitochondrial membrane potential, reactive oxygen species (ROS) formation, malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) activity suggested that anti-cancer action of LA is due to enhanced ROS generation and decreased cell anti-oxidant capacity that resulted in mitochondrial damage. Of the three cell lines tested, semi-differentiated colorectal cancer cells RKO were most sensitive to the cytotoxic action of LA, followed by undifferentiated colorectal cancer cell line (LOVO) while the normal human umbilical vein endothelial cells (HUVEC) were the most resistant (the degree of sensitivity to LA is as follows: RKO > LOVO > HUVEC). LA induced cell death was primed by mitochondrial apoptotic pathway. Pre-incubation of cancer cells with 100 μM LA for 24 hr enhanced sensitivity of differentiated and semi-differentiated cells to the subsequent exposure to LA. The relative resistance of LOVO cells to the cytotoxic action of LA is due to a reduction in the activation of caspase-3. Thus, LA induced cancer cell apoptosis by enhancing cellular oxidant status and inducing mitochondrial dysfunction.

Topics: Apoptosis; Caspase 3; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Linoleic Acid; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondrial Diseases; Osmolar Concentration; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase

Polyunsaturated fatty acids (PUFAs) possess anti-cancer action both in vitro and in vivo. In the present study, we detected cell viability with methyl thiazolyl tetrazolium (MTT) assay and cell membrane permeability with propidium iodide (PI) fluorescence dyeing, and calculated cell membrane fluidity change as fluorescence anisotropy. Fatty acid content in cells was measured by gas chromatography/mass spectroscopy (GC/MS), and the relationship between fatty acid composition and cell viability was studied. We observed that n-6 PUFA linoleic acid (LA) inhibited tumor cell growth at high concentrations (≥300 µmol/L), while low concentrations (100-200 µmol/L) seemed to promote cell proliferation. Analyses of cell membrane permeability, cell membrane fluidity, and cell fatty acid composition suggested that the anti-cancer action of LA could be related to changes in the ratio of n-6 to n-3 PUFAs. We observed that pre-incubation of cancer cells with 100 µmol/L LA for 24 h enhanced cell sensitivity to the cytotoxic action of LA, whereas undifferentiated cell line LoVo seemed to have a distinct path in LA-induced death. These results showed that one of the mechanisms by which supplementation of LA induces cancer cell death could be altering the ratio of n-6/n-3 PUFAs, and this may be related to cell differentiation status.

Topics: Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Colorectal Neoplasms; Fatty Acids; Humans; Linoleic Acid; Membrane Fluidity

15-LOX-1 and its metabolites are involved in colorectal cancer. Recently, we reported that 15-LOX-1 overexpression in HCT-116 human colorectal cancer cells inhibited cell growth by induction of p53 phosphorylation (4). To determine whether the 15-LOX-1 protein or its metabolites are responsible for phosphorylation of p53 in HCT-116 cells, we used HCT-116 cells that expressed a mutant 15-LOX-1. The mutant 15-LOX-1 enzyme, with a substitution of Leu at residue His361, was devoid of enzymatic activity. HCT-116 cells transiently transfected with either native or mutant 15-LOX-1 showed an increase in p53 phosphorylation and an increase in the expression of downstream genes. Thus, 15-LOX-1 induces p53 phosphorylation independent of enzymatic activity. Treatment of A549 human lung carcinoma cells with IL-4 increased the expression of 15-LOX-1 and also increased the expression of downstream targets of p53. This confirmed that the activation of p53 was also observed in wild-type cells expressing physiological 15-LOX-1. Immunoprecipitation experiments revealed that 15-LOX-1 interacts with, and binds to, DNA-dependent protein kinase (DNA-PK). The binding of 15-LOX-1 to DNA-PK caused an approximate 3.0-fold enhancement in kinase activity, resulting in increased p53 phosphorylation at Ser15. Knockdown of DNA-PK by small interfering RNA (siRNA) significantly reduced p53 phosphorylation. Furthermore, confocal microscopy demonstrated a colocalization of 15-LOX and DNA-PK in the cells. We propose that the 15-LOX-1 protein binds to DNA-PK, increasing its kinase activity and results in downstream activation of the tumor suppressor p53, thus revealing a new mechanism by which lipoxygenases (LOX) may influence the phenotype of tumor cells.

Topics: Arachidonate 15-Lipoxygenase; Blotting, Western; Colorectal Neoplasms; DNA; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Immunoprecipitation; Linoleic Acid; Lung Neoplasms; Phenotype; Phosphorylation; Protein Kinases; RNA, Small Interfering; Transfection; Tumor Suppressor Protein p53

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

Polyunsaturated free fatty acids (PUFAs) participate in normal functioning of the cell, particularly in control intracellular cell signalling. As nutritional components they compose a human diet with an indirect promoting influence on tumourogenesis. The PUFAs level depends on the functional state of the membrane. This work is focused on changes only of free unsaturated fatty acids amount (AA - arachidonic acid, LA - linoleic acid, ALA - alpha-linolenic acid, palmitoleic acid (PA) and oleic acid) in cell membranes of colorectal cancer of pT3 stage, G2 grade without metastasis. Qualitative and quantitative composition of free unsaturated fatty acids in the membrane was determined by high-performance liquid chromatography. It was shown that the malignant transformation was accompanied by a decrease in amount of LA and ALA while arachidonic and oleic acids increased. It is of interest that free AA levels are elevated in colon cancer, as AA is the precursor to biologically active eicosanoids.

Topics: Aged; Aged, 80 and over; alpha-Linolenic Acid; Arachidonic Acid; Cell Membrane; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Humans; Linoleic Acid; Male; Middle Aged; Neoplasm Staging

The present study systematically explored metabolic pathways and altered expressions of genes speculatively participating in colorectal carcinogenesis by using a Microarray-Bioinformatic analysis methods. The results revealed that 157 genes were up-regulated and 281 genes were down-regulated in colorectal cancer (CRC). Gene Ontology (GO) and relevant bioinformatics tools indicated that the functional category to which 438 genes (12%; 438/3800) of the most frequent alteration belonged was metabolism. The analysis of 10 colorectal cancer tissue specimens demonstrated that genes involved in fatty acid metabolic pathways had high rates of overexpression. In addition, we stimulated CRL-1790 cell line with linoleic acid (a polyunsaturated fatty acid) for 12, 24, 48 and 72 h. Cell proliferation was elevated by 5, 25, 28 and 31% (P<0.05), respectively. Further analyses revealed that the genes increasingly expressed in the cell line included enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase (EHHADH), enoyl Coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1); glutaryl-Coenzyme A dehydrogenase (GCDH), acyl-Coenzyme A oxidase 2, branched chain (ACOX2); acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain precursor (ACADS); carnitine palmitoyltransferase 1B (CPT1B), acyl-CoA synthetase long-chain family member 5 (ACSL5), and cytochrome P450, family 4, subfamily A, and polypeptide 11 (CYP4A11) genes. This indicated that the stimulating effect of linoleic acid on cell proliferation was due to interference with the metabolic pathway of fatty acid metabolism. In conclusion, genes with altered expression levels in CRC were mainly associated with fatty acid metabolic pathways speculated to have an important role linked to carcinogenesis.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Proliferation; Colorectal Neoplasms; Computational Biology; Fatty Acids; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Linoleic Acid; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Signal Transduction

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.

Topics: Adenoviridae; Arachidonate 15-Lipoxygenase; Colorectal Neoplasms; Down-Regulation; Humans; Linoleic Acid; Linoleic Acids; Oxidation-Reduction; PPAR delta; PPAR gamma; PPAR-beta

The activation of peroxisome proliferator activated receptor gamma (PPARgamma) may play a role in the control of colorectal carcinogenesis. The expression of PPARgamma was examined by Western blotting in human colorectal tumors and matched normal adjacent tissues, as well as in various colorectal carcinoma cell lines. In the tissues, the expression of PPARgamma was elevated in tumors relative to the adjacent normal tissues. Each colorectal carcinoma cell line expressed PPARgamma. The ability of various eicosanoids to bind PPARgamma in colorectal carcinoma cells was investigated using luciferase reporter assays. The well-known PPARgamma ligands, troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2) strongly induced PPARgamma binding activity. Products of lipoxygenases displayed moderate binding activity, while other prostaglandins and fatty acids displayed little or no reporter activation. The activation of PPARgamma by 13(S)-HODE, the major metabolite of 15-lipoxygenase-1 from linoleic acid, was concentration dependent reaching maximum at 10 micro M (35-fold activation). The endogenous production of 13(S)-HODE by expression of 15-LO-1 did not activate PPARgamma. The ability of various nonsteroidal anti-inflammatory drugs (NSAIDs) to induce PPARgamma activation was also evaluated. The conventional NSAIDs that inhibit both cyclooxygenases (COX-1 and COX-2) also induced PPARgamma binding activity. In general, however, neither COX-1- nor COX-2-specific inhibitors induced the activation of PPARgamma. Taken together, the metabolites of 15-lipoxygenase and the conventional NSAIDs were confirmed as exogenous ligands for PPARgamma in colorectal carcinoma cells.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Caco-2 Cells; Cell Line, Tumor; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Eicosanoids; Electrophoresis, Polyacrylamide Gel; Genetic Vectors; Humans; Ligands; Linoleic Acid; Linoleic Acids; Luciferases; Protein Binding; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Uptake and incorporation of long-chain fatty acids were studied in a human colorectal cancer cell line (HT29/219) grown in culture medium supplemented with either fetal calf serum (FCS) or horse serum (HS). The cells were grown for 120 h with no change of medium; the two major cellular lipid classes, the phospholipids and the triacylglycerols, were analyzed at regular time-points. We observed significant changes in the concentration of most fatty acids throughout culture, and differences in their composition when different sera were used to supplement the medium. Minimal levels of free fatty acids were found in the cells, indicating a very small "free fatty acid pool". A major difference between the cells grown in media supplemented with different sera was the changes observed in concentrations of cellular polyunsaturated fatty acids during growth. In cells grown with FCS (in which 20:4n-6 is present), the levels of this acid in the phospholipid and triacylglycerol fractions declined rapidly during cell growth, suggesting further metabolism. In cells grown in medium supplemented with HS, 18:2n-6 was the major polyunsaturated acid present. There was clear evidence that this acid accumulated in the cellular triacylglycerol and phospholipid fractions. Furthermore, its concentration did not decline during growth in culture, suggesting minimal conversion to other polyunsaturated n-6 acids. Our results suggest that fatty acids from additional sources in the medium, for example triacylglycerols and phospholipids associated with the lipoproteins, are taken up by the cells. There is also indication of cellular fatty acid synthesis, particularly of monounsaturated and saturated acids during the culture period.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-Linolenic Acid; Arachidonic Acid; Cell Division; Colorectal Neoplasms; Culture Media; Fatty Acids; Fatty Acids, Unsaturated; Humans; Kinetics; Linoleic Acid; Linoleic Acids; Linolenic Acids; Oleic Acid; Oleic Acids; Phospholipids; Triglycerides; Tumor Cells, Cultured

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