Traditional Processed Meat Products Re-designed Towards Inulin-rich Functional Foods Reduce Polyps in Two Colorectal Cancer Animal Models.

Inulin-rich foods exert a prebiotic effect, as this polysaccharide is able to enhance beneficial colon microbiota populations, giving rise to the in situ production of short-chain fatty acids (SCFAs) such as propionic and butyric acids. These SCFAs are potent preventive agents against colorectal cancer due to their histone deacetylases inhibitory properties, which induce apoptosis in tumor colonocytes. As colorectal cancer is the fourth most common neoplasia in Europe with 28.2 new cases per 100,000 inhabitants, a cost-effective preventive strategy has been tested in this work by redesigning common porcine meat products (chorizo sausages and cooked ham) consumed by a substantial proportion of the population towards potential colorectal cancer preventive functional foods. In order to test the preventive effect of these inulin-rich meat products against colorectal cancer, an animal model (Rattus norvegicus F344) was used, involving two doses of azoxymethane (10 mg/kg) and two treatments with dextran sodium sulfate (DSS) during a 20-week assay period. Control feed, control sausages, functional sausages (15.7% inulin), control cooked ham and functional cooked ham (10% inulin) were used to feed the corresponding animal cohorts. Then, the animals were sacrificed and their digestive tract tissues were analyzed. The results showed a statistically significant 49% reduction in the number of colon polyps in the functional meat products cohorts with respect to the control meat products animals, as well as an increase in the cecum weight (an indicator of a diet rich in prebiotic fiber), a 51.8% increase in colon propionate production, a 39.1% increase in colon butyrate concentrations, and a reduction in the number of hyperplastic Peyer's patches. Metagenomics studies also demonstrated colon microbiota differences, revealing a significant increase in Bacteroidetes populations in the functional meat products (mainly due to an increase in Bacteroidaceae and Prevotellaceae families, which include prominent propionate producers), together with a reduction in Firmicutes (especially due to lower Lachnospiraceae populations). However, functional meat products showed a remarkable increase in the anti-inflammatory and fiber-fermentative Blautia genus, which belongs to this Lachnospiraceae family. The functional meat products cohorts also presented a reduction in important pro-inflammatory bacterial populations, such as those of the genus Desulfovibrio and Bilophila. These results were corroborated in a genetic animal model of CRC (F344/NSlc-Apc1588/kyo) that produced similar results. Therefore, processed meat products can be redesigned towards functional prebiotic foods of interest as a cost-effective dietary strategy for preventing colorectal cancer in human populations.

De Novo Development of Hamartomatous Duodenal Polyps in a Patient With Short Bowel Syndrome During Teduglutide Therapy: A Case Report.

Teduglutide (TG) is approved for the treatment of parenteral nutrition (PN)-dependent adult patients with short bowel syndrome (SBS). Its well-known adverse effect is expedited growth of colon polyps and potential formation of new polyps. Apart from animal studies, de novo development of duodenal polyps in a patient during TG therapy has not been reported in the literature. We report a case of a 71-year-old man with SBS on TG who developed multiple new duodenal polyps that were found incidentally during a diagnostic endoscopy. Furthermore, an accelerated growth of duodenal polyps was noted while on TG therapy, suggesting a potential trophic effect of TG on these polyps. There are no current recommendations for the surveillance of intestinal polyps in patients on TG therapy, but we recommend exercising caution and possible need for surveillance based on this case report.

Association between colorectal polyps and hypertension treatment.

OBJECTIVE: Patients who take drugs regularly are increasing, not least due to metabolic and orthopedic diseases. In the present study we aimed to investigate the association between the use of drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin, and colorectal polyps diagnosed based on colonoscopic findings. METHODS: In total, 1318 consecutive patients who underwent total colonoscopy for the first time were cross-sectionally analyzed. Personal data including comorbidities and all medications were obtained by a questionnaire. Their blood pressure, body weight and waist circumference were measured just before the colonoscopic examination. RESULTS: Colorectal polyps were found in 577 (43.8%) patients, with a prevalence of 57.6% (296/514) in patients receiving antihypertensive treatment and 35.0% (281/804) in patients not undergoing such treatment. A multivariate analysis showed that age, waist circumference, alcohol consumption, smoking and the use of antihypertensive drugs were independent risk factors for colorectal polyps. In a secondary multivariate analysis incorporating the parameters of measured blood pressure and medication status, the number of antihypertensive drugs was strongly associated with the risk of colorectal polyps, whereas blood pressure showed no significant association. CONCLUSIONS: The use of antihypertensive drug may be a risk factor for colorectal polyps. Furthermore, this risk increases with the intensive use of antihypertensive drugs.

Insulin therapy and colorectal adenomas in patients with diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (DM) are at increased risk for colorectal adenomas and cancer because of endogenous hyperinsulinemia. Exogenous insulin therapy has been associated with higher colorectal cancer incidence. The aim of this study was to evaluate the association between exogenous insulin therapy and adenoma formation, accounting for duration of therapy and location and stage of the adenoma. METHODS: We conducted a cross-sectional study of patients with type 2 diabetes between the ages of 50 and 80 years who completed full colonoscopies. Cases were patients with any adenoma on index colonoscopy. Patients without any adenoma composed the control group. Multivariable logistic regression was used to calculate odds ratios (OR) and associated confidence intervals (CI). RESULTS: Compared with the controls, case patients (n = 196) did not have a significantly increased odds of insulin exposure, when exposure was defined as 12 months or more of insulin use compared with no insulin. However, the odds of insulin exposure among the cases was significantly increased when exposure was defined as 18 months or more (OR 1.6, 95% CI 1.1-2.5), 24 months or more (OR 1.7, CI 1.1-2.6), and 36 months or more (OR 2.0, 95% CI 1.2-3.4) of insulin use (test for trend P = 0.05). A similar trend in insulin exposure was seen among type 2 diabetics with advanced adenomas. Adenoma location was not significantly affected by insulin therapy. CONCLUSIONS: Chronic insulin therapy is associated with increased risk of colorectal adenomas in patients with type 2 diabetes. IMPACT: Diabetes patients receiving insulin may need more stringent colon cancer screening.

Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression.

Peroxisome proliferator-activated receptor (PPAR) delta is a member of the nuclear hormone receptor superfamily. PPARdelta may ameliorate metabolic diseases such as obesity and diabetes. However, PPARdelta's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARdelta decreases intestinal adenoma growth in Apc(Min/+) mice and inhibits tumor-promoting effects of a PPARdelta agonist GW501516. More importantly, we found that activation of PPARdelta up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K-Akt signaling. These results not only highlight concerns about the use of PPARdelta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARdelta antagonists for prevention and/or treatment of cancer.

Inhibition of intestinal carcinogenesis by a new flavone derivative, chafuroside, in oolong tea.

A new flavone derivative, chafuroside, has been isolated as a strong anti-inflammatory compound from oolong tea leaves, and its structure determined to be (2R,3S,4S,4aS,11bS)-3,4,11-trihydroxy-2-(hydroxymethyl)-8-(4-hydroxyphenyl)-3,4,4a,11b-tetrahydro-2H,10H-pyrano[2',3':4,5]furo[3,2-g]chromen-10-one. To assess its potential to inhibit intestinal carcinogenesis, 2.5, 5 and 10 p.p.m. chafuroside was given in the diet to Apc-deficient Min mice for 14 weeks from 6 weeks of age. Total numbers of polyps were reduced to 83, 73 and 56% of the control value, respectively. Moreover, dietary administration at 10 and 20 p.p.m. reduced azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) development in rats to 69% of the AOM-treated control value with the higher dose. Chafuroside-associated toxicity was not observed at 2.5-10 p.p.m. in Min mice and 10-20 p.p.m. in AOM-treated rats. These results suggest that chafuroside might be a good chemopreventive agent for colon cancer.

Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis.

Accumulating evidence indicates that overproduction of prostanoids attributable to overexpression of cyclooxygenase-2 (COX-2) plays an important role in colon carcinogenesis. We have shown recently that the prostaglandin (PG) E receptor, EP(1), but not EP(3), is involved in mouse colon carcinogenesis. In line with our previous study, here we examined the role of prostanoid receptors in colon carcinogenesis using six additional lines of knockout mice deficient in prostanoid receptors EP(2), EP(4), DP, FP, IP, or TP. The animals were treated with the colon carcinogen, azoxymethane (AOM), and examined for the development of aberrant crypt foci (ACFs), putative preneoplastic lesions in the colon. Formation of ACFs was decreased only in the EP(4)-knockout mice, to 56% of the wild-type level. To confirm these results, we also examined the inhibitory effects of an EP(4)-selective antagonist, ONO-AE2-227, in the diet on the formation of AOM-induced colon ACFs in C57BL/6Cr mice and on the development of intestinal polyps in Min mice. ONO-AE2-227 at a dose of 400 ppm reduced the formation of ACFs to 67% of the control level, and intestinal polyp numbers in Min mice receiving 300 ppm were decreased to 69% of the control level. Plating efficiency assays showed that addition of 1.0 microM ONO-AE1-329, an EP(4)-selective agonist, resulted in a 1.8-fold increase in the colony number of the human colon cancer cell line, HCA-7, similar to the effect of PGE(2). Moreover, EP(4) mRNA expression was clearly observed in normal colon mucosa and colon tumors in mice. Our previous and present results indicate that PGE(2) contributes to colon carcinogenesis through its actions mediated through EP(1) and EP(4) receptors; therefore, antagonists for these two receptors may be good candidates as chemopreventive agents against colon cancer.

Milk and dairy products in cancer prevention: focus on bovine lactoferrin.

Milk and dairy products constitute an important part of the western style diet. A large number of epidemiological studies have been conducted to determine effects of consumption on cancer development but the data are largely equivocal, presumably reflecting the different included components. It has been proposed that whereas fats in general could promote tumor development, individual milk fats like conjugated linoleic acid could exert inhibitory effects. There is also considerable evidence that calcium in milk products protects against colon cancer, while promoting in the prostate through suppression of circulating levels of 1,25-dihydroxyvitamin D3. Whey protein may also be beneficial, as shown by both animal and human studies, and experimental data have demonstrated that the major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the post-initiation stage in male F344 rats treated with azoxymethane (AOM) without any overt toxicity. The incidence of adenocarcinomas in the groups receiving 2% and 0.2% bLF were thus 15% and 25%, respectively, in contrast to the 57.5% control value (P<0.01 and P<0.05, respectively). Results in other animal models have provided further indications that bLF might find application as a natural ingredient of milk with potential for chemoprevention of colon and other cancers.

Phenolphthalein-containing laxative use in relation to adenomatous colorectal polyps in three studies.

Phenolphthalein, the active ingredient in many laxatives, was recently found to be a carcinogen in animal models. Human data suggest a laxative-colon cancer association, but few data specifically address the effects of phenolthalein-containing laxatives. We examined use of phenolphtalein-containing laxatives in relation to occurrence of adenomatous colorectal polyps in data from three case-control studies. The study conducted in Los Angeles, California (1991-1993), and the two studies conducted in North Carolina (1988-1990 and 1992-1995) altogether included 866 cases and 1,066 controls. The prevalence of using phenolphthalein-containing laxatives at least once a week in the recent past, however, was less than 5% among these subjects. The multivariate-adjusted odds ratios associated with recent use of phenolphthalein-containing laxatives once a week or more were 1.8 -95% confidence interval (CI), 0.5-6.2] in Los Angeles, 1.0 (CI, 0.4-2.2) in North Carolina (1988-1990), and 1.1 (CI, 0.2-5.7) in North Carolina (1992-1995). For use of other types of laxatives, the corresponding odds ratios were 1.3 (CI, 0.9-1.9) in Los Angeles, 1.0 (CI, 0.5-1.7) in North Carolina (1988-1990), and 0.9 (CI, 0.4-1.8) in North Carolina (1992-1995). Although the low prevalence of frequent use made for relatively wide confidence intervals, overall these data suggest that use of phenolphthalein-containing laxatives does not increase risk of adenomatous colorectal polyps.

Effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on intestinal polyp development in Apc delta 716 knockout mice.

Damage to the human adenomatous polyposis coli (APC) gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract. Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice with a truncation mutation in the Apc gene. These heterozygous mice developed intestinal polyps. We found that all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating loss of heterozygosity (LOH) (Oshima et al., Proc. Natl. Acad. Sci. USA 92:4482-4486, 1995). Using these knockout mice, we investigated the effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), one of the most abundant heterocyclic amines found in cooked meat and fish. When PhIP was fed to these mice at 400 ppm for 8 wk, the polyp distribution shifted to a larger size range, although the total polyp number did not change significantly. Similar, but weaker, effects were observed with the other heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. On the other hand, intraperitoneal injections of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhlP) at a higher dose (50 mg/kg) for five consecutive days increased the polyp number significantly. This increment was not associated with mutations in the Apc gene; however, most polyps showed loss of the full-length Apc allele (LOH). These results suggest that PhIP affects intestinal polyp development by accelerating the growth rate of microadenomas. It is also possible that high doses of N-OH-PhIP increase the frequency of Apc gene LOH.

Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice.

Capsaicin was administered in a semisynthetic powdered diet at 0.03125% level for the lifespan of Swiss mice starting from 6 weeks of age. As a result of C treatment, tumors of the cecum were induced in 22% of females and 14% of males, whereas the corresponding tumor incidences in untreated female and male controls were both 8%. Histopathologically, the tumors were classified as benign polypoid adenomas. Capsaicin is the main pungent principle of hot pepper, which is consumed in high quantities by humans worldwide. The capsaicin content of some chili varieties ranges up to 0.53%.

Bromodichloromethane, a trihalomethane that produces neoplasms in rodents.

Bromodichloromethane, a trihalomethane found in water supplies after chlorination, was administered by gavage in corn oil to male and female F344/N rats and B6C3F1 mice for up to 2 years at dose levels of 0, 50, or 100 mg/kg to rats, 0, 25, or 50 mg/kg to male mice, and 0, 75, or 150 mg/kg to female mice. Survival at 2 years in rats and in male mice was comparable among groups and was greater than 50% at the termination of the experiment. Survival in female mice was greater than 50% in all groups until week 84 but was reduced toward the end of the study because of ovarian abscesses in some female mice. There was clear evidence of carcinogenicity in males and females of both species as shown by increased incidences of tubular cell adenomas and adenocarcinomas in the kidney and adenocarcinomas and adenomatous polyps in the large intestine in male and female rats, increased incidences of tubular cell adenomas and adenocarcinomas in the kidney of male mice, and increased incidences of hepatocellular adenomas and carcinomas in female mice. Of the three trihalomethanes studied to date in the National Cancer Institute/National Toxicology Program (chloroform, chlorodibromomethane, or bromodichloromethane) bromodichloromethane caused the widest spectrum of neoplasms in rodents.

Promoting effects of bile acid to intestinal tumorigenesis in gnotobiotic ICR mice.

Gnotobiotes were produced by administrating Lactobacillus plantarum IAM 1041 in ICR strain male germfree mice which were fed by ordinary or high fat diet. Both groups were orally administered 0.3 mg/10 g of body weight (B.W.) of methylazoxymethanol (MAM) acetate. The oral administration of 0.3 mg/10 g/B.W. once a week for 11 consecutive weeks caused a total of 68 adenomatous polyps in the large intestine (an average of 11.4/mouse) of gnotobiotic high fat diet mice and a total of 32 adenomatous polyps (an average of 5.3/mouse) of the ordinary diet mice. There were no malignancies in either of the groups. Bile acids in the feces showed higher values in the high fat diet group than in the ordinary group. Bile acids are a factor which promotes the appearance of intestinal tumors. It was also assumed that the L. plantarum promoted the activation of beta-glucuronidase and alcohol dehydrogenase in the liver and intestine.

Stimulation of chemically induced rectal carcinogenesis by chronic ethanol ingestion.

The effect of chronic ethanol administration on 1, 2-dimethylhydrazine-induced rectal carcinogenesis was investigated in 32 paired male Sprague-Dawley rats fed a nutritionally-adequate liquid diet containing 36% of the total calories as either ethanol or isocaloric carbohydrates. Chronic ethanol ingestion increased the total number of rectal tumors significantly (17 vs 6; P less than 0.02), whereas no cocarcinogenic effect of ethanol was observed in other parts of the intestine. Alcohol did not influence tumor size or histopathology. A 47% increase in the activity of mucosal alcohol dehydrogenase in the distal colorectal region was found between chronically-ethanol-fed rats and pair-fed controls (0.241 +/- 0.019 vs 0.164 +/- 0.020 mumol/mg of protein/hr; P less than 0.01). This could in part explain the cocarcinogenic effect of alcohol in this tissue. Faecal bile acids, however, do not play a role as promotors of rectal carcinogenesis under the present experimental conditions. The results give experimental support to the epidemiologic findings of an increased incidence of rectal cancer in the alcoholic.

[Vitamin C in a long-term trial is without effect on experimental carcinogenesis]. / Vitamin C im Langzeitversuch ohne Einfluss auf die experimentelle Carcinogenese.

This long-term study deals with the effect of ascorbic acid on chemically induced carcinogenesis of the small intestine in rats. Carcinoma was induced in 27 animals by application of N-Ethyl-N'-nitro-N-nitrosoguanidine (ENNG) alone in the drinking water (120 mg/1). The average survival time was 238 ( 40) days. The addition of large amounts of ascorbic acid to the food (3 g/100 g food) did not suppress the development of tumors. On the contrary, a significant reduction in the survival time was seen. All animals receiving ENNG and ascorbic acid only lived 207 ( 45) days on average. Neither histological type of tumor spread was influenced by the use of ascorbic acid. Giving ascorbic acid alone had no effect on the survival time and did not lead to changes in the tissue of the small intestine.

Enhancement of 1,2-dimethylhydrazine-induced rectal carcinogenesis following chronic ethanol consumption in the rat.

The incidence, distribution, size, and histopathology of grossly visible intestinal tumors induced by the parenteral administration of 1,2-dimethylhydrazine dihydrochloride were examined in 32 paired rats fed a nutritionally adequate liquid diet containing 36% of total calories either as ethanol or isocaloric carbohydrates. The liquid diets were begun 4 wk before the first of four weekly injections of 1,2-dimethylhydrazine dihydrochloride. At the time of the subcutaneous application of the procarcinogen, liquid diets were omitted for 3 wk, and were replaced by a standard laboratory diet. This feeding schedule was repeated four times, and after 32 wk the animals were killed. Chronic ethanol ingestion increased the total number of rectal tumors significantly (17 vs. 6, p less than 0.02). However, alcohol had no effect on tumor size or histopathology. Chronic ethanol ingestion did not exhibit any cocarcinogenic effect in tissues other than the rectum. A 47% increase in the activity of mucosal alcohol dehydrogenase in the distal colorectum was found between chronically ethanol-fed rats and pair-fed controls (0.241 +/- 0.019 vs. 0.164 +/- 0.020 mumol X mg protein-1 X h-1, p less than 0.01). This could in part explain the cocarcinogenic effect of alcohol in this tissue. Fecal bile acids, however, do not play a role as promoters of rectal cancer under the present experimental conditions. The data give experimental support to the epidemiologic findings of an increased incidence of rectal cancer in the alcoholic.