Number Of Colonic Polyps Research Articles

Exercise Affects Mucosa-Associated Microbiota and Colonic Tumor Formation Induced by Azoxymethane in High-Fat-Diet-Induced Obese Mice.

The only reliable factor that reduces the risk of colorectal carcinogenesis is physical activity. However, the underlying mechanisms remain unclear. In this study, we examined the effects of physical activity against gut microbiota, including mucosa-associated microbiota (MAM) on azoxymethane-induced colorectal tumors in obese mice. We divided the subjects into four groups: normal diet (ND), high-fat diet (HFD), ND + exercise (Ex), and HFD + Ex groups. The Ex group performed treadmill exercise for 20 weeks. Thereafter, fecal and colonic mucus samples were extracted for microbiota analysis. DNA was collected from feces and colonic mucosa, and V3-V4 amplicon sequencing analysis of the 16SrRNA gene was performed using MiSeq. The HFD group had significantly more colonic polyps than the ND group (ND 6.5 ± 1.3, HFD 11.4 ± 1.5, p < 0.001), and the addition of Ex suppressed the number of colonic polyps in ND and HFD groups (ND 6.5 ± 1.3, ND + Ex 2.8 ± 2.5, p < 0.05). The HFD group showed significantly lower concentrations of succinic, acetic, butyric, and propionic acids (mg/g) in feces, compared with the ND group (succinic acid HFD 0.59, ND 0.17; acetic acid HFD 0.63, ND 2.41; propionic acid HFD 0.10, ND 0.47; and N-butyric acid HFD 0.31, ND 0.93). In the case of ND, succinic acid and butyric acid tended to decrease with Ex (succinic acid ND 0.17, ND + Ex 0.12; N-butyric acid ND 0.93, ND + Ex 0.74 0.74). Succinic acid, acetic acid, butyric acid, and propionic acid levels in feces were significantly lower in the HFD group than in the ND group; in both feces and mucus samples, Butyricicoccus and Lactobacillus levels were significantly lower in the HFD group. Akkermansia was significantly increased in ND + Ex and HFD + Ex groups. Diet and exercise affected the number of colorectal tumors. Furthermore, diet and exercise alter intestinal MAM, which may be involved in colorectal tumor development.

An exploration of the effect of Chinese herbal compound on the occurrence and development of large intestine cancer and intestinal flora

This study was conducted to observe the effect of Chinese herbal compound on the treatment of colon cancer using AOM/DSS-induced C57BL/6J colon cancer mice and to validate potential influence on intestinal flora of mice. A colorectal cancer (CRC) mouse model was built with a total of 50 C57BL/6J mice that were induced by administrating AOM/DSS. These experimental animals were split up into 5 groups, a control group, a model group, and low-, medium- and high-dose Chinese herbal compound groups. All mice were given Chinese herbal compound treatment, and the colon tissues of each group were harvested with the length measured and the number of colon polyps accounted. The Ki-67 expression in the colon tissues was detected via immuno-histochemistry. Relative quantification of the expression of genes and proteins was determined through qPCR and WB assays. Contents of IL-6, TNF-α, IFN-γ, and IL-10 in serum and colon tissues of mice were determined by ELISA. An additional 16S rRNA sequencing analysis was implemented for the identification of mouse intestinal flora. The results suggested that all low-, medium- or high-dose Chinese herbal compound could markedly inhibit the shortening of colon length and significant number reduction of colon polyps in the model group. The relative expression of genes and proteins (PCNA, Muc16, and MMP-9) associated with proliferation in mouse colon tissues were inhibited. In addition, compared with the model group, the contents of IL-6, TNF-α, and IFN-γ in serum and colon tissues were substantially decreased in the high-dose Chinese herbal compound group, thereby reducing the structure damage in colon tissues and the infiltration degree of inflammatory cells. Besides, the expression of TLR4/MyD88/NF-κB protein was markedly decreased. The 16S rRNA sequencing analysis demonstrated that mice in the model group had decreased intestinal flora diversity, and there were significant changes in flora abundance and amino acid metabolism between the control group and the model group. Taken together, the treatment of Chinese herbal compound against CRC in this study might be regulated by the TLR4/MyD88/NF-κB signaling pathway, and the imbalance in intestinal flora was also closely related to CRC occurrence.

Evidence for diet-gene interaction in early-onset colorectal cancer.

182 Background: About 10 percent of all colorectal cancers are in subjects who are not yet 50 (EO-CRC) and the occurrence of early onset colorectal cancer (EO-CRC) is rising in the US. Patients with CRC are twice as likely to have diabetes or be overweight. Using targeted exome sequencing of germline DNA from EO-CRC subjects, we identified a missense mutation at Ala98Val within the DNA binding domain of Hepatic Nuclear Factor 1 alpha (HNF1A, 12q24.31, Rs1800574). HNF1A is the most frequently mutated gene in diabetic individuals whose onset of diabetes occurs typically before age 25 (MODY3 locus). Our aim was to demonstrate that the HNF1A variant provides a genomic landscape for EO-CRC to develop in the setting of a specific diet type. Methods: HNF1A was identified using targeted exon sequencing of archived leukocyte DNA from subjects with EO-CRC. Flag-tagged WT and HNF1AA98V expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts were prepared for Electrophoretic Mobility Shift Assays (EMSAs) to test binding differences. An Hnf1aA98V mutant mouse model was generated using CRISPR/Cas9. WT, Hnf1a A98V/+ and Hnf1a A98V/A98V mice were placed on 3 diets--normal chow, a high fat (~34%) diet (HFD) or a high sugar (~62% fructose) diet (HSD) after weaning at 3 weeks. The mice were followed for 12 months, weighed monthly, and observed for clinical signs of morbidity. After euthanizing, blood, colon and liver were collected for histology and qPCR. Results: HNF1AA98V was identified in 13/145 subjects with EO-CRC. An additional 3 subjects exhibited mutations elsewhere in HNF1A. Flag-tagged WT and mutant HNF1A-expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts showed reduced HNF1AA98V binding to its consensus DNA element by EMSA. Only heterozygous or homozygous Hnf1aA98V mice on the HFD showed a significant number of colon polyps (~19%). Only 1/22 heterozygous mice developed a polyp on the HSD. RNA-Seq analysis of colonic mucosa from the homozygous mutant compared to WT mice revealed an increase lipid and b-catenin regulated genes. Specifically, there was an increase in β-catenin, LEF 1 and MYC by immunohistochemistry in the polyp of HNF1AA98V, but not in the adjacent normal tissue. Liver steatosis in the Hnf1aA98V versus WT mice on the HFD was observed. Conclusions: Occurrence of the HNF1AA98V variant is increased among a cohort of EO-CRC patients and is a loss of function mutation that creates a genetic landscape for colon polyps on a HFD.

Berberine inhibits high fat diet-associated colorectal cancer through modulation of the gut microbiota-mediated lysophosphatidylcholine.

Dietary fat intake is positively associated with elevated risk of colorectal cancer (CRC). Currently, clinical treatments remian inadequate bacause of the complex pathogenesis of CRC induced by a high-fat diet (HFD). Mechanistically, imbalances in gut microbiota are associated with HFD-associated colorectal tumourigenesis. Therefore, we investigated the anti-tumor activity of berberine (BBR) in modulating the dysregulated gut microbiota and related metabolites by preforming 16S rDNA sequencing and liquid chromatography/mass spectrometry. As expected, BBR treatment significantly decreased the number of colonic polyps, ameliorated gut barrier disruption, and inhibited colon inflammation and related oncogenic pathways in AOM/DSS-induced CRC model mice fed with an HFD. Furthermore, BBR alleviated gut microbiota dysbiosis and increased the abundance of beneficial gut microorganisms, including Akkermansia and Parabacteroides, in HFD-fed CRC mice. In addition, metabolomics analysis demonstrated significantly altered the glycerophospholipid metabolism during the progression of HFD-associated CRC in mice, whereas BBR treatment reverted these changes in glycerophospholipid metabolites, particularly lysophosphatidylcholine (LPC), which was confirmed to promote CRC cell proliferation and ameliorate cell junction impairment. Notably, BBR had no clear anti-tumor effects on HFD-fed CRC model mice with gut microbiota depletion, whereas transplantation of BBR-treated gut microbiota to gut microbiota-depleted CRC mice recapitulated the inhibitory effects of BBR on colorectal tumourigenesis and LPC levels. This study demonstrated that BBR inhibited HFD-associated CRC directly through modulating gut microbiota-regulated LPC levels, thereby providing a promising microbiota-modulating therapeutic strategy for the clinical prevention and treatment of Western diet-associated CRC.

Difference in the prevalence of advanced colon adenoma between patients with gastric neoplasm and healthy people: A STROBE-compliant study.

We compared the prevalence of adenoma and cancerous colon polyps in patients undergoing endoscopic removal or gastric surgery for gastric adenoma or gastric cancer and in healthy individuals.The medical records of 707 patients with gastric neoplasm and 798 age- and sex-matched healthy subjects were retrospectively analyzed between January 2010 and July 2018. The clinicopathological characteristics, prevalence of colorectal neoplasm diagnosed by colonoscopy, and risk factors for colorectal polyps were also investigated.When comparing the two groups, the prevalence of overall colorectal polyps and its distribution was not different between the two groups (54.0% vs.49.5%, P = .079), whereas, the number of colon polyps (1.20 ± 1.71 vs 0.99 ± 1.54, P = .015) and the maximal size (3.53 ± 6.14 vs 2.08 ± 2.88, P < .001) were significantly larger in the gastric neoplasm group. The prevalence of advanced colon adenoma was significantly higher in the gastric neoplasm group (10.7% vs 3.8%, P < .001). Risk factors such as elevated glucose levels and the presence of gastric neoplasm were related to the prevalence of all colon polyps. The presence of gastric neoplasm is an important risk factor for advanced colon polyps.Patients with gastric neoplasms had a significantly higher prevalence of advanced colon adenoma. Advanced colon adenoma is associated with the chain from benign adenomas through malignant altered adenomas to advanced colon cancer. Thus, patients with gastric neoplasm are regarded as a high-risk group for colorectal cancer and are recommended for screening colonoscopy at the time of diagnosis.

Colonoscopic Polypectomy: Analysis of 429 cases

Aim: It is well known that most colorectal cancers develop from colon polyps. Therefore, removing polyps found during colonoscopy, regardless of their size and characteristics, is critical because of the risk of developing colorectal cancer. This study aimed to evaluate the outcomes of colonoscopic polypectomy performed in our clinic. Materials and Methods: The data of patients who underwent colonoscopy for various reasons between January 2018 and December 2020 and who had polypectomy performed during the procedure were evaluated retrospectively. These patients were divided into two groups, single polypectomy, and multiple polypectomy cases. Results: Single polyp was detected in 72% (n=309) of the 429 patients included in the study, whereas multiple polyps were detected in 28% (n=120). Of these patients, 62.9% (n=270) were male and 37.1% (n= 159) were female. The median age of patients with a single polyp (61,0) was lower than that of patients with multiple polyps (65,0) (p= 0.014). In patients with a single polyp, the most common localization was rectum (32.4%), and the most common histopathological subtype was tubular adenoma (50.8%). In patients who underwent multiple polypectomies, the most common localization was a sigmoid colon (25.5%), while the most common histopathological subtype was again tubular adenoma (48.1%). There was no statistically significant difference between the two groups in the severity of dysplasia (p = 0,838). A significant difference was found between polyp diameter and dysplasia severity in adenomatous polyps in both groups (p&lt;0.001). Conclusion: Colonoscopic polypectomy effectively reduces the risk of colorectal cancer by removing precancerous polyps. Colon polyps are often prominent in the rectosigmoid region and more common in the male gender. An increase in the number of colon polyps is observed with age. In our country, a multicenter prospective study with many participants is required to characterize polyps.

S‐Allylcysteine Inhibits PhIP/DSS‐Induced Colon Carcinogenesis through Mitigating Inflammation, Targeting Keap1, and Modulating Microbiota Composition in Mice

ScopeThe objective of the present study is to investigate whether edible S‐allylcysteine (SAC) has chemoprophylactic effects on inflammation‐associated colon carcinogenesis induced in mice through 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) exposure and promoted by dextran sodium sulfate (DSS) and whether its cancer‐prevention effects are related to the modulation of gut microbiota composition.Methods and resultsDietary administration of 0.05% SAC in mice for 18 weeks prevents shortening of the colon length and reduces the number of colon polyps. The SAC supplementation markedly decreases PhIP/DSS‐induced plasma and colon tissue pro‐inflammatory cytokines. These changes are accompanied by the suppression of inducible nitric oxide synthase, COX‐2, and MMP‐2 protein expression in colon tissue. In addition, the dietary administration of SAC increases heme oxygenase‐1 expression through activation of the NF‐E2‐related factor 2 pathway, thus abating PhIP/DSS‐induced colitis. The 16S rRNA gene sequence data indicate that SAC counteracted the PhIP/DSS‐induced gut dysbiosis, resulting in a microbiota composition similar to the control group.ConclusionThe results indicate that SAC can suppress PhIP/DSS‐induced colorectal carcinogenesis. Hence, SAC may merit further clinical investigation as a chemoprevention strategy for retarding colitis‐associated colon cancer in humans.

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.

Utility of Mesalazine in Familial Adenomatous Polyposis: Clinical Report of Reduction of Polyp Size in Patients with Ulcerative Colitis, and Safety Examination in Familial Adenomatous Polyposis Patients

Mesalazine is the gold standard drug for treatment of ulcerative colitis (UC). Here, we describe 4 cases of familial adenomatous polyposis (FAP) patients with UC that showed reduction of intestinal polyp diameter by mesalazine treatment. Of note, the effects of mesalazine on the development of intestinal polyps in FAP patients have not been reported, and we further investigated whether the short-term use of high-dose mesalazine (4 g/day) has harmful effects on FAP patients or not. The authors found that the treatment showed slightly adverse events in FAP patients. However, mesalazine tended to reduce the number of colon polyps in male subjects with FAP. This report provides basic information for planning a double-blind, randomized, clinical trial that aims to show mesalazine’s potential to suppress intestinal polyp development in FAP.

Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a hereditary predisposition to formation of colon polyps that can progress to colorectal cancer (CRC). The severity of polyposis varies substantially within families bearing the same germline mutation in the adenomatous polyposis coli (APC) tumour suppressor gene. The progressive step-wise accumulation of genetic events in tumour suppressor genes and oncogenes leads to oncogenic transformation, with driver alterations in the tumour protein p53 (TP53) gene playing a key role in advanced stage CRC. We analysed groups of pigs carrying a truncating mutation in APC (APC1311/+; orthologous to human APC1309/+) to study the influence of TP53 polymorphisms and expression on the frequency of polyp formation and polyp progression in early-stage FAP. Five generations of APC1311/+ pigs were examined by colonoscopy for polyposis severity and development. A total of 19 polymorphisms were found in 5′-flanking, coding, and 3′ untranslated regions of TP53. The distribution of TP53 genotypes did not differ between APC1311/+ pigs with low (LP) and high (HP) number of colon polyps. p53 mRNA expression was analysed in distally located normal mucosa samples of wild-type pigs, APC1311/+ LP and HP pigs, and also in distally located polyp samples histologically classified as low-grade (LG-IEN) and high-grade intraepithelial dysplastic (HG-IEN) from APC1311/+ pigs. p53 mRNA expression was found to be significantly elevated in HG-IEN compared to LG-IEN samples (p = 0.012), suggesting a role for p53 in the early precancerous stages of polyp development.

Chemopreventive effect of Myricetin, a natural occurring compound, on colonic chronic inflammation and inflammation-driven tumorigenesis in mice

Myricetin is a flavonoids compound extracted from edible myrica rubra. We aimed to evaluate the efficacy of Myricetin on colonic chronic inflammation and inflammation-driven tumorigenesis in mice. Myricetin was administrated by gavage for 4 consecutive weeks. Mice were sacrificed and the number of colonic polyps was counted. Myricetin significantly inhibited AOM/DSS-induced colitis and colorectal tumorigenesis. Myricetin prevented the incidence of colorectal tumorigenesis and reduced the size of colorectal polyps. Histopathologic analysis showed that Myricetin could attenuate the degree of colonic inflammation and colorectal tumorigenesis. Further analysis showed that Myricetin strongly reduced the levels of inflammatory factors TNF-α, IL-1β, IL-6, NF-κB, p-NF-κB, cyclooxygenase-2 (COX-2), PCNA and Cyclin D1 in the colonic tissues as analyzed by the assays of immunohistochemical staining, Western blotting and Q-RT-PCR. Our results demonstrated that Myricetin possesses the biological activities of chemoprevention colonic chronic inflammation and inflammation-driven tumorigenesis. We suggest that Myricetin could be developed as a promising chemopreventive drug for reducing the risk of colorectal cancer.

Long-chain ω-6 plasma phospholipid polyunsaturated fatty acids and association with colon adenomas in adult men: a cross-sectional study.

Dietary lipid intake can be associated with an increased risk for colorectal cancer depending on its composition. Carcinogenesis alters lipid metabolism to facilitate cell growth and survival. For instance, metabolites of polyunsaturated fatty acids (PUFAs) are associated with increasing colon cell proliferation. Moreover, precancerous colon lesions (i.e. adenomas) increase the risk for colorectal cancer. In this study, we investigated associations between plasma PUFAs and the number of colon polyps and polyp type (i.e. hyperplastic and adenoma). Healthy male participants (n=126) of 48-65 years of age were recruited before a routine colonoscopy screening. Plasma phospholipid (PPL) PUFAs were isolated by means of solid phase extraction and methylated. Fatty acid methyl esters were analyzed using gas chromatography. Factor analysis was used to cluster PUFAs into groups, and then generated factors and individual PUFAs were analyzed using polytomous logistic regression. In our age-adjusted and smoking-adjusted polytomous logistic regression, for each unit increase in PPL docosatetraenoic acid (DTA), individuals were 1.43 (1.00-2.06) and 1.33 (0.99-1.80) times more likely to have hyperplastic polyps and adenomas rather than no polyps, respectively. In our factor analysis, high PPL ω-6 PUFA and trans-fatty acid loading scores were associated with increased odds of adenoma presence rather than no polyps. Increases in long-chain PPL ω-6 PUFAs are associated with an increased risk for adenomas. As relative levels of DTA increase in PPLs, individuals had increased odds of having hyperplastic polyps and adenomas. Elevated conversion of ω-6 PUFAs to longer-chain ω-6s such as DTA may indicate altered PUFA metabolism at the tissue level.

Clinical Characteristics, Prevalence, and Complications of Colonic Diverticular Disease in an Urban Hispanic Population

Introduction: Diverticulitis and Diverticular bleeding, which are complications of Diverticular Disease, are the leading gastrointestinal indication for hospitalization in the United States. Diverticular Disease is well studied in White populations with average rates of Diverticulosis of 25% along with Diverticulitis in 15-20%, and Diverticular Bleeding in 5-15% of those affected. There is limited data on Hispanic populations with Diverticular Disease. This study will aim to define the clinical characteristics of a Hispanic population to determine risk factors for Diverticular Disease and its complications. Methods: This is a retrospective study that analyzed medical records and endoscopic reports from a tertiary center with a predominantly Hispanic population. Hispanic patients were identified through ethnicity reports in the Endoscopic database and sorted into confirmed diverticulosis by colonoscopy and presence and number of colonic polyps. Age, gender, BMI, use of non-steroidal anti-inflammatory drugs (NSAID), tobacco, alcohol, presence of co-morbidities, and complications such as Diverticular bleeding and Diverticulitis were assessed through chart review. Data was analyzed with multivariable logistic regression. Results: A total of 491 inpatient and outpatient endoscopy and electronic medical record charts between June through September 2016 were reviewed. 372 of the patients were Hispanic and included in the study. 119 of the 372 Hispanic patients had presence of Diverticulosis confirmed on colonoscopy report, with a prevalence of 31.7%. Increasing Age 58.3 vs 53.5 (P=0.004; 95% CI 1.012-1.065), BMI 31.6 vs 28.9 (P=0.002; 95% CI 1.020-1.095), and NSAID use (P=0.048; 95% CI 1.005-2.714) were associated with the presence of Diverticulosis. Increasing number of colonic polyps 1.38 vs 1.13 (P=0.047 95% CI 1.015-2.721) was also seen in those with Diverticulosis. 51% had left sided disease (n=61) vs 9.2% right sided (n=11) vs. 39% pan-colonic (n=47). Diverticular complications included 18.5% with hematochezia (n=22) and 11% with Diverticulitis (n=13). Conclusion: High prevalence of Diverticulosis is seen in Hispanics with mostly left sided and pan-colonic disease that are associated with colonic polyps. Increasing age, BMI, and NSAID can be predictive of the presence of Diverticulosis in Hispanics. Higher rates of Diverticular bleeding and equivalent rates of Diverticulitis were seen compared to past literature of White populations.

Abdominal obesity as the colorectal adenomas risk factor

Obesity is a risk factor for many diseases, including colorectal cancer. Aim: to study association of the constitutional features (height, weight, waist circumference) with detection of colon polyps on the screening colonoscopy. Materials and methods: Constitutional features (height, weight, waist circumference) of 145 patients were assessed with detection of colon polyps on the screening colonoscopy for the period from 2013to 2015. Exclusion criteria were: cancer of any location in history, surgery within the past two years, the inflammatory bowel diseases (Crohn's disease, ulcerative colitis), autoimmune diseases (rheumatoid arthritis, HIV, AIDS, SLE), diabetes, chronic liver or kidney disease, family polyposis. Results: the presence of adenomas (OR = 6.0 CI: 2,2-16,7); multiplicity of polyps (the possibility that there will be ≥ 3 polyps was 6.4, CI: 1,4-29,9) were significantly higher in obese patients than in those with normal weight. Subjects with a waist circumference in the highest tertile (>115 cm), were 4.6 times more likely to identify ≥ 3 polyps than those with waist circumference in the lowest tertile (<96 cm) . The probability of detection of adenomas in patients with a waist circumference in the highest tertile were 6.2 times higher than in the lowest tertile. Conclusions. Visceral obesity is associated with a morphological type and number of colon polyps. The presence of visceral obesity significantly increases the risk of colon adenomas. Increased visceral fat layer is an indication for colonoscopy especially of the right half of the colon examination. Screening colonoscopy should be recommended for the obese patients after 50 y.o. in order to diagnose adenomas of the colon and colorectal cancer.

Abstract A05: Immunity, the colonic environment, and colon cancer

Abstract Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the US. Evidence from several studies suggests that the colonic immune environment can influence the risk of CRC. Bacterial minicells (MC) are spherical, non-viable nano-sized particles derived from genetically-engineered E. coli (Vaxiion Therapeutics, Inc). MC contain all of the components of parental bacteria they are derived from with the exception of the chromosome, making them non-infectious. MC used here have been engineered to display antitumor activity via integrin-specific cytotoxic effects but evidence suggests they also require a working immune system to be optimally effective in mouse models of cancer. For our colon cancer studies, we are using an immune-competent mouse model, FABP-CreXApcfl/+, which has a conditional deletion of exons 11-12 in one Adenomatous Polyposis Coli (Apc) allele in the epithelium of colon and distal ileum, due to the targeted expression of CRE, leading to colonic polyposis. Hypothesis: Since MC have been shown to have anti-cancer activity in multiple mouse models, but even more importantly because evidence suggests they are more effective in animals with a functional immune system, we hypothesize that MC can change the immune environment of the colon and delay/decrease the onset of colon cancer in our mouse model. Methods: We treated 14 week old FABP-CreXApcfl/+ mice with PBS or 1.5 x 109 MC in PBS intra-rectally once a week until 19 weeks of age (6 treatments total). Mice were then left untreated until 26 weeks of age, euthanized, and colons were collected to measure tumor number and size. Colonic tumor load was also compared to 24 week old untreated FABP-CreXApcfl/+ controls. RNA was isolated from tumor adjacent (TA), small tumor (≤4mm) and large tumor (&amp;gt;4 mm) tissue, converted to cDNA, and qPCR studies were performed. Hprt was used as a housekeeping gene control and fold-change target gene expression was reported in comparison to Hprt expression. Results: The mean number of colonic polyps in 26 week old mice that received MC-treatment during the 14th-19th week of age was significantly lower (2.4±1.5) in comparison with mice that received PBS only (9.3±1.4, p=0.03) or 24 week-old untreated controls (8.0±1.9, p=0.02). Moreover, MC-treatment significantly restricted the development of colonic polyps &amp;gt;4mm in size (0.6±0.2/mouse, i.e. 60% of mice had one large tumor each) in comparison to PBS-treated (3.7±0.8/mouse, p=0.03) and 24 week-old untreated (2.0±0.2/mouse, p=0.01) controls. Furthermore, as per qPCR studies, preliminary work suggests that MC promote the expression of TH1 and cytotoxic T cell-associated immune responses (CD8a, Tbet, Ifng, perforin) as well as the TH17 (Il17a) immune gene marker in the TA areas of the colon. We also found a decline in the expression of pro-inflammatory (il23, Il6), immunosuppressive (Il10, Foxp3) and immune cell recruitment (Cx3cl1) immune markers in the large tumors of MC-treated mice. Furthermore, our preliminary data suggest the presence of ‘low’ and ‘high’ responders in MC-treated mice. ‘Low responders’ have at least one large tumor at 26 weeks of age and lower correlation of TH1 and cytotoxic T cell-associated immune responses in comparison to ‘high responders’ which have an absence of large tumors and display multi-fold higher levels of TH1 and cytotoxic T cell-associated immune responses in comparison to PBS-treated controls. Conclusion: MC significantly delay the development of colonic polyps and our preliminary data suggest that the delay/decrease in tumorigenesis could be because of attenuation of pro-tumor inflammation as well as promotion of anti-tumor immunity in the colon. These studies also suggest our mouse model will be appropriate for the study of low and high responder anti-tumor immune phenotypes in mice, shedding light on what may be occurring in human CRC patients. Citation Format: Mohammad W. Khan, Shingo Tsuji, MengXi Tian, Nairika Meshgin, Shea Grenier, Matthew J. Giacalone, Kathleen L. McGuire. Immunity, the colonic environment, and colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A05.

Abstract C68: Decreased antitumor cytotoxic immunity in African American colon cancer

Abstract Background: African Americans (AA) have a higher incidence of colorectal cancer (CRC) and more aggressive disease than patients of other ethnicities. Several studies have suggested that biological/genetic factors contribute to this health disparity. Recent work has shown the importance of the immune system to cancer patient prognosis, for CRC in particular. Anti-tumor T helper 1 (TH1) cell activation of cytotoxic T lymphocytes (CTL) increases CRC patient disease-free survival while deficiencies in these responses correlate with a worse prognosis. We hypothesize that differences in anti-tumor immunity by race contribute to the disparity and lead to more aggressive CRC in AA patients. Methods: Over 250 human colon tumors samples were stained using immunohistochemistry to evaluate in situ immune cell infiltration (CD8 and CD57), CTL activity [granzyme B (GzmB)], and IL-17 production. Also, using GzmB immunostaining, we analyzed the histological location of CTL/Natural Killer (NK) cell activity at intratumoral vs. invasive border sites of the CRC samples. In addition, a colon cancer mouse model is being used to identify mechanisms that may alter TH1 and CTL activity in developing tumors. The mouse model is the TS4Cre x APCfl-468 conditional Adenomatous Polyposis Coli (APC) knockout. Exons 11 and 12 are deleted from one APC gene in the colon and distal ileum due to the expression of CRE under a Fatty acid binding protein promoter leading to polyposis. These colonic tumors are being evaluated using qPCR on immune and inflammatory gene products. Results: Our studies on human microsatellite stable colon cancer samples showed that the number of CD8+ and CD57+ tumor-infiltrating cells doesn't differ by race (p=0.83 and 0.32, respectively). The level of GzmB+ cells, i.e. CTLs and activated NK cells, however, does vary significantly by race (p=0.01), particularly at the invasive border (p=0.0006). The numbers of IL-17A producing cells do not vary (p=0.63) but IL-17 may modulate GzmB correlation with CD8 and CD57 by race. For example, in AA, the correlation between GzmB and CD8 drops from 0.80 in IL-17Ahigh samples to 0.53 in IL-17Alow samples. For GzmB and CD57, the correlation level drops from 0.51 to 0.28 between IL-17A-high and -low samples, respectively. No such drop in correlation is observed in Caucasian American samples. In our mouse model, our preliminary studies show the TS4CRExAPCfl-468 mice initiate colonic polyposis at ~18 weeks of age and invasive cancer is observed in 20-25% of mice older than 31 weeks. The mean number of colonic polyps significantly increases between 18 and 24 weeks (from 2.3±0.9 to 8.0±1.9 tumors/mouse). Interestingly, the number declines by 36 weeks of age (5.5±0.5 tumors/mouse). However, the mean size of the colonic polyps significantly increases from 18 weeks to 36 weeks of age (from 1.54mm±0.55 to 4.23mm±0.56). To determine what mechanisms might result in lower anti-tumor CTL/NK activity, mouse tumors at different stages of development are currently being evaluated for IL-27, GzmA, IL-23, ƔIFN, CD8, Perforin, CX3CL1, IL-17a, H2DMB2, and Tbet gene expression using qPCR. Primers sets are also being developed to include IL-4, IL-6, IL-10, IL-12p40, and FoxP3 in our analyses. Conclusion: Our data to date indicate that the number of AA patients with high numbers of GzmB expressing cells infiltrating their tumors is significantly lower than Caucasians. In addition, IL-17 may have a modulatory effect on anti-tumor cytotoxicity by race. These observations support our hypothesis that immune processes contribute to the racial disparities observed in CRC. Current studies in our mouse model of CRC should identify mechanisms decreasing anti-tumor CTL/NK cell activity that will be tested in our Caucasian and AA colon cancer patient tumor samples in future studies. Note: This abstract was not presented at the conference. Citation Format: Mohammad W. Khan, MengXi Tian, John M. Carethers, Kathleen L. McGuire. Decreased antitumor cytotoxic immunity in African American colon cancer. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C68.

Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

Proton radiotherapy is becoming more common since protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared to conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIR) which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence associated gene (P19Arf) are markedly increased. Following these changes loss of Casein kinase Iα (CKIα) and induction of chronic DNA damage and TP53 mutations are increased compared to x-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, CDDO-EA, reduces proton irradiation associated SIR and tumorigenesis. Thus, exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

Next-generation narrow band imaging system for colonic polyp detection: a prospective multicenter randomized trial.

Previous studies have yielded conflicting results on the colonic polyp detection rate with narrow-band imaging (NBI) compared with white-light imaging (WLI). We compared the mean number of colonic polyps detected per patient for NBI versus WLI using a next-generation NBI system (EVIS LUCERA ELITE; Olympus Medical Systems) used with standard-definition (SD) colonoscopy and wide-angle (WA) colonoscopy. this study is a 2 × 2 factorial, prospective, multicenter randomized controlled trial. this study was conducted at five academic centers in Japan. patients were allocated to one of four groups: (1) WLI with SD colonoscopy (H260AZI), (2) NBI with SD colonoscopy (H260AZI), (3) WLI with WA colonoscopy (CF-HQ290), and (4) NBI with WA colonoscopy (CF-HQ290). the mean numbers of polyps detected per patient were compared between the four groups: WLI with/without WA colonoscopy and NBI with/without WA colonoscopy. Of the 454 patients recruited, 431 patients were enrolled. The total numbers of polyps detected by WLI with SD, NBI with SD, WLI with WA, and NBI with WA were 164, 176, 188, and 241, respectively. The mean number of polyps detected per patient was significantly higher in the NBI group than in the WLI group (2.01 vs 1.56; P = 0.032). The rate was not higher in the WA group than in the SD group (1.97 vs 1.61; P = 0.089). Although WA colonoscopy did not improve the polyp detection, next-generation NBI colonoscopy represents a significant improvement in the detection of colonic polyps.

Colonization of the Human Gut by E. coli and Colorectal Cancer Risk

The intestinal microbiota is potentially involved in the development of colorectal carcinoma via various mechanisms. Escherichia coli are commensal bacteria of the human gut microbiota, but some pathogenic strains have acquired the ability to induce chronic inflammation and/or produce toxins, such as cyclomodulin, which could participate in the carcinogenesis process. Here, we analyzed the E. coli population associated with mucosa of patients with colon cancer in relation to clinicopathologic characteristics. We assessed carcinogenic properties of a colon cancer-associated E. coli strain in multiple intestinal neoplasia (Min) mice. Mucosa-associated or internalized E. coli were quantified and characterized from tumors and mucosa of patients with colon cancer and the healthy mucosa of diverticulosis controls. Min mice were inoculated with a colon cancer-associated E. coli strain (11G5). The number of colonic polyps was evaluated at 7 weeks after infection. An increased level of mucosa-associated and internalized E. coli was observed in the tumors compared with normal tissue. A relationship between poor prognostic factors for colon cancer (tumor-node-metastasis stage) and colonization of mucosa by E. coli was observed. Pathogenic cyclomodulin-positive E. coli strains were more prevalent on mucosa of patients with stages III/IV than those with stage I colon cancer. Proliferative index and E. coli colonization level of the mucosa distant from the tumor significantly correlated. Min mice infected with the E. coli strain 11G5 displayed a marked increase in the number of visible colonic polyps compared with controls. These findings support that pathogenic E. coli could be a cofactor in pathogenesis of colorectal cancer.

Regression of Colonic Adenomas After Treatment With Sulindac in Familial Adenomatous Polyposis: A Case With a 2-Year Follow-up Without a Prophylactic Colectomy.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by hundreds of colorectal adenomatous polyps that progress to colorectal cancer. Management of patients with FAP is with a total colectomy. Chemopreventive strategies have been studied in FAP patients in an effort to delay the development of adenomas in the upper and the lower gastrointestinal tract and to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery. Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of colorectal adenomas in the retained rectal segment of FAP patients. However, evidence regarding long-term use of this therapy and its effect on the intact colon has been insufficient. We report a case in which the long-term use of sulindac was effective in reducing the size and the number of colonic polyps in patients with FAP without a prophylactic colectomy and polypectomy; we also present a review of the literature.