Risk Factor For Colon Cancer Research Articles

A prospective evaluation of plasma polyphenol levels and colon cancer risk.

Polyphenols have been shown to exert biological activity in experimental models of colon cancer; however, human data linking specific polyphenols to colon cancer is limited. We assessed the relationship between pre‐diagnostic plasma polyphenols and colon cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Using high pressure liquid chromatography coupled to tandem mass spectrometry, we measured concentrations of 35 polyphenols in plasma from 809 incident colon cancer cases and 809 matched controls. We used multivariable adjusted conditional logistic regression models that included established colon cancer risk factors. The false discovery rate (q values) was computed to control for multiple comparisons. All statistical tests were two‐sided. After false discovery rate correction and in continuous log2‐transformed multivariable models, equol (odds ratio [OR] per log2‐value, 0.86, 95% confidence interval [95% CI] = 0.79–0.93; q value = 0.01) and homovanillic acid (OR per log2‐value, 1.46, 95% CI = 1.16–1.84; q value = 0.02) were associated with colon cancer risk. Comparing extreme fifths, equol concentrations were inversely associated with colon cancer risk (OR = 0.61, 95% CI = 0.41–0.91, p trend = 0.003), while homovanillic acid concentrations were positively associated with colon cancer development (OR = 1.72, 95% CI = 1.17–2.53, p trend < 0.0001). No heterogeneity for these associations was observed by sex and across other colon cancer risk factors. The remaining polyphenols were not associated with colon cancer risk. Higher equol concentrations were associated with lower risk, and higher homovanillic acid concentrations were associated with greater risk of colon cancer. These findings support a potential role for specific polyphenols in colon tumorigenesis.

National Cancer Societies and their public statements on alcohol consumption and cancer risk.

Studies have shown that alcohol consumption is a risk factor for oral, pharyngeal, laryngeal, esophageal, liver, colon, rectal and breast cancer. It would therefore be expected that cancer prevention organizations would incorporate these facts into their public stance on the consumption of alcohol. The aims of this study were to: (1) assess how national cancer societies in developed English-speaking countries [i.e. English-speaking countries belonging to the Organization for Economic Co-operation and Development (OECD)] communicate alcohol-related cancer risk to the public and (2) compare whether these organization's advocacy of increased alcohol taxes is in line with their advocacy of tobacco tax increases to reduce cancer risk. We searched the websites of the following national cancer organizations for all statements related to the relationship between alcohol consumption and cancer risk: Cancer Council Australia, Canadian Cancer Society, Irish Cancer Society, Cancer Society New Zealand, Cancer Research UK and the American Cancer Society. A categorical system was developed to code the qualitative data for health statements, alcohol consumption recommendations, and tax policy recommendations. Websites were analyzed in March of 2017. All organizations, with the exception of the American Cancer Society and Canadian Cancer Society, state that alcohol is a group 1 carcinogen and that even low-level alcohol consumption increases risk for some cancers. Additionally, while the American Cancer Society supports increasing tobacco taxes through its cancer action network, it has not advocated for increased alcohol taxes in relation to support for tobacco tax increases. Analysis in 2017 of the websites for national cancer societies in Australia, Canada, Ireland, New Zealand, the United Kingdom and the United States-including Cancer Council Australia, the Canadian Cancer Society, the Irish Cancer Society, Cancer Society New Zealand, Cancer Research UK and the American Cancer Society-shows that only the American Cancer Society and Canadian Cancer Society websites fail to state that alcohol is a group 1 carcinogen and can cause cancer at low doses, and that there is no safe threshold for cancer risk.

The benefits of primary prevention of colorectal cancer around the age of 20 compared to secondary prevention after the age of 50

The major advantages of primary prevention of colorectal cancer in young adults (around 20 years) compared with se condary prevention in adults (after 50 years). Primary prevention is aimed at screening and eliminating one of the major proven risk factors for colon cancer – chronic constipation and its predecessor – colorectal bradyarrhythmia – as slower circadian rhythm of defecation. The main advantages of primary prevention of colorectal cancer are: non-invasiveness, safety, efficiency and timeliness. Screening of colorectal bradyarrhythmia at 2501 operating physician is allowed to diagnose this arrhythmia in 44% of the surveyed entities. There is discovered the new fundamental dependence between the regularity of circadian rhythm of defecation and an acrophase of this rhythm. The implementation of the morning acrophase of the circadian rhythm of defecation is the key mechanism of the regularity of this rhythm. Repeated screening of colorectal bradyarrhythmia in individuals around the age of 20 years (a month after informing students about the law of circadian rhythm in the brain and intestine) showed that 53% of the students began to observe the morning routine of bowel movements. This led to a transition of moderate stage of colorectal bradyarrhythmia severity (3-4 times a week) in an easy stage (5-6 times a week). It’s proved the possibility of primary (behavioral) prevention of colorectal bradyarrhythmia (colorectal coprostasis) as a risk factor for colorectal cancer. Secondary prevention of colon cancer is associated with the invasiveness of colonoscopy, its possible complications (bleeding, perforation of bowel and fatal outcomes), the high cost of special equipment and late in the approach to screening for colorectal cancer (after the appearance of blood in the stool or after 50 years).

ROLE OF ASPIRIN AS PROPHYLAXIS AGAINST COLORECTAL CANCER

Introduction: Colorectal cancer (Bowel Cancer) is cancer of colon and rectum that are the parts of large intestine. [1] Symptoms are pain on defecation, blood and mucus in feces.[2] Risk factors of colon cancer are certain diet that is red meat, alcohol, and meat that is processed, obesity, smoking, and lack of physical activity.[3, 4]. Others factors are old age, type three personalities and usage of spicy foods. People with inflammatory bowel disease (ulcerative colitis and Crohn's disease), familial adenomatous polyposis are at high threat of cancer of colon and rectum. This can be prevented by using aspirin usage in long term.[5,6,7]. In high danger families, cancer of colon can be prevented by using aspirin and colonoscopies are recommended in these families.[8,9] Colorectal cancer can be diagnosed by sigmoidoscopy or colonoscopy.[10,11,12] .Most of people (50 %) do not report any signs and symptoms of colon cancer.[13,14]. Streptococcus gallolyticus is associated with colorectal cancer.[15, 16]&#x0D; Objective: To find out the role of aspirin as prophylaxis against colorectal cancer.&#x0D; Methodology: This descriptive retrospective study was conducted in the Ibnae –Sienna Hospital Multan from January 2016 to August 2017. 100 patients of each group between 50-65 years of age were included in the study; all were male whose were taken aspirin for pain killer and for fever as routine since long term and 100 male patients of same age not used aspirin. Date analysis was carried out using SPSS version 19 Software. Results: All were male patients 100 (100 %) 50-65 years of age. Most of the patients (98) 98 % who used aspirin in the past have no colorectal cancer as compared to patients (18) 18 % who not taken aspirin in the past have colorectal cancer.&#x0D; Conclusion: Patients used aspirin since long have very least possibilities of colorectal cancer

Crohn's Disease: General characteristics and treatment with Adalimumabe biopharmaceutical

Crohn's Disease (CD) is a chronic inflammatory disease that affects the gastrointestinal system. The etiology is not fully understood, however, genetic, immunological, microbiological and environmental factors are related to its genesis. The most common manifestations of this disease are diarrhea, abdominal pain, ulcers and fistulas. In the absence of adequate treatment it can evolve into extra intestinal complications and is also an important risk factor for colon and rectal cancer. The treatment of the disease is palliative and there is no cure for the disease, being considered only the period of remission of symptoms, as a good prognosis. The biopharmaceutical, Adalimumabe, produced by recombinant DNA technology has demonstrated efficacy in the treatment of this disease, as it prevents the action of TNF-α, a cytokine involved in inflammation and is abundant in individuals with CD. Although Adalimumabe has good results, its use leads to side effects that can be mild or fatal, such as the activation of tuberculosis.

Increased colon cancer risk after severe Salmonella infection.

BackgroundColon cancer constitutes one of the most frequent malignancies. Previous studies showed that Salmonella manipulates host cell signaling pathways and that Salmonella Typhimurium infection facilitates colon cancer development in genetically predisposed mice. This epidemiological study examined whether severe Salmonella infection, usually acquired from contaminated food, is associated with increased colon cancer risk in humans.Methods and findingsWe performed a nationwide registry-based study to assess colon cancer risk after diagnosed Salmonella infection. National infectious disease surveillance records (1999–2015) for Dutch residents aged ≥20 years when diagnosed with salmonellosis (n = 14,264) were linked to the Netherlands Cancer Registry. Salmonella-infected patients were laboratory-confirmed under medical consultation after 1–2 weeks of illness. These datasets also contained information on Salmonella serovar and type of infection. Colon cancer risk (overall and per colon subsite) among patients with a diagnosed Salmonella infection was compared with expected colon cancer risk in the general population. Data from the nationwide registry of histo- and cytopathology (PALGA) and Statistics Netherlands (CBS) allowed assessing potential effects of age, gender, latency, socioeconomic status, genetic predisposition, inflammatory bowel disease (IBD), and tumor features. We found that compared to the general population, colon cancer risk was significantly increased (standardized incidence ratio [SIR] 1.54; 95%CI 1.09–2.10) among patients with Salmonella infection diagnosed <60 years of age. Such increased risk concerned specifically the ascending/transverse colon (SIR 2.12; 95%CI 1.38–3.09) after S. Enteritidis infection (SIR 2.97; 95%CI 1.73–4.76). Salmonellosis occurred more frequently among colon cancer patients with pre-infectious IBD, a known risk factor for colon cancer. Colon tumors of patients with a history of Salmonella infection were mostly of low grade.ConclusionsPatients diagnosed with severe salmonellosis have an increased risk of developing cancer in the ascending/transverse parts of the colon. This risk concerns particularly S. Enteritidis infection, suggesting a contribution of this major foodborne pathogen to colon cancer development.

Nicotine increases colon cancer cell migration and invasion through epithelial to mesenchymal transition (EMT): COX-2 involvement.

Cigarette smoking is a recognized risk factor for colon cancer and nicotine, the principal active component of tobacco, plays a pivotal role in increasing colon cancer cell growth and survival. The aim of this study was to determine the effect of nicotine on cellular Caco-2 and HCT-8 migration and invasion, focusing on epithelial to mesenchymal transition (EMT) induction, and COX-2 pathway involvement. In both these cell lines, treatment with nicotine increased COX-2 expression and the release of its enzymatic product PGE2 . Moreover, nicotine-stimulated cells showed increased migratory and invasive behavior, mesenchymal markers up-regulation and epithelial markers down-regulation, nuclear translocation of the β-catenin, increase of MMP-2 and MMP-9 activity, and enhanced NF-κB expression. Noticeably, all these effects are largely mediated by COX-2 activity, as simultaneous treatment of both cell lines with nicotine and NS-398, a selective COX-2 inhibitor, greatly reduced the number of migrating and invading cells and reverted nicotine-induced EMT. These findings emphasize that nicotine triggers EMT, leading hence to increased migration and invasiveness of colon cancer cells. Thereby, the use of COX-2 inhibitor drugs might likely counteract nicotine-mediated EMT effects on colon cancer development and progression.

Serum Levels of TRIM72 Are Lower among Patients with Colon Cancer: Identification of a Potential Diagnostic Marker.

Colon cancer is one of the most common malignancies causing the majority of cancer-related deaths worldwide. The tripartite motif family protein 72 (TRIM72), also known as mitsugumin 53, acts as an E3 ubiquitin ligase. TRIM72 is involved in insulin resistance and metabolic syndrome, which are risk factors of colon cancer. However, the correlation between TRIM72 and colon cancer remains unknown. In the present study, we explored the expression profile of TRIM72 in colon cancer tissues and the diagnostic value of serum TRIM72 in colon cancer. The receiver operating characteristic (ROC) curves were applied for evaluating the diagnostic value of serum TRIM72. We thus found that immunoreactive TRIM72 levels were significantly lower in colon cancer tissues than those in normal colon tissues. Moreover, serum TRIM72 levels were significantly lower in colon cancer patients than those in healthy volunteers. Importantly, the lower serum TRIM72 levels were associated with advanced clinical stage, lymph node, and distant metastases in colon cancer patients. The ROC curve analysis showed that serum TRIM72 has a superior diagnostic value (the area under the curve (AUC) = 0.829) than the traditional tumor biomarkers, carcinoembryonic antigen (CEA) (AUC = 0.707) and carbohydrate antigen 19-9 (CA199) (AUC = 0.750), and the combination of TRIM72 with CEA and CA199 showed the best diagnostic value for colon cancer (AUC = 0.928). In conclusion, serum TRIM72 may be a potential biomarker for the diagnosis and the prognosis of colon cancer.

SRC and TP53 play critical role in low-grade dysplasia colorectal mucosa transformation into cancer.

Determination of crucial genes that are involved in onset and progress of dysplasia of colorectal mucosa is the aim of this study. Management of dysplasia as one of the risk factors of colon cancer is very challenging. Molecular studies could be helpful in this matter. Here, the transcriptome profile of low-grade dysplasia in colon tissue in comparison with normal one is studied by protein-protein interaction (PPI) network analysis. For detecting differentially expressed genes (DEGs) of dysplasia lesion, the data was downloaded from the gene chip GSE31106, platform GPL1261, GSM770092-94 as normal colorectal mucosa group and GSM770098-100 as low-grade dysplasia colorectal mucosa from the Gene Expression Omnibus database (GEO). The expression profile is evaluated by GEO2R and a network of DEGs is constructed and analyzed by Cytoscape algorithms. The findings indicate that a PPI network analysis of 113 DEGs is consist of 8 nodes that 6 of them are common with inflammation state. Only SRC and TP53 were recognized as the specific makers for dysplasia. In this respect, a subnetwork of these two genes introduce a panel of 8 nodes consist of HRAS, MYC, PIK3CA, PIK3CB, PIK3CD, PIK3CG, SRC, and TP53. It can be concluded that SRC and TP53 may play prominent role in dysplasia pathogenicity after running validation tests.

Integrated Analysis Reveals That Long Non-Coding RNA TUBA4B Can Be Used as a Prognostic Biomarker in Various Cancers

Background/Aims: Recent studies have reported the importance of tubulin alpha 4b (TUBA4B), a long non-coding RNA, in the development of several cancers; however, studies on its clinical significance are rare. In the present meta-analysis, we investigated whether TUBA4B can be used as a prognostic biomarker in human cancers. Methods: A comprehensive search was performed in PubMed, Embase, Web of Science, and the Gene Expression Omnibus databases. Hazard ratios from individual studies were calculated and pooled using a random-effects or fix-effects model. The pooled hazard ratio (HR) with 95% confidence interval (CI) was used to evaluate the value of TUBA4B. The expression of TUBA4B was evaluated in lung cancer tissue arrays by fluorescence in situ hybridization assay. Additionally, a sensitivity analysis and Begg’s test were conducted. Results: We found that TUBA4B was significantly correlated with overall survival (OS) (HR = 1.33, 95% CI: 1.16–1.52, P=0.000), disease-free survival (DFS; HR = 1.25, 95% CI: 1.06–1.48, P=0.007), and recurrence-free survival (RFS; HR = 1.42, 95% CI: 1.26–1.60, P=0.000). In addition, TUBA4B was a risk factor for lung cancer (HR = 1.24, 95% CI: 1.03–1.49, P=0.021), colon cancer (HR = 1.67, 95% CI: 1.02–2.74, P=0.042), breast cancer (HR = 1.52, 95% CI: 1.10–2.12, P=0.012), and ovarian cancer (HR = 1.67, 95% CI: 1.18–2.36, P=0.004). Moreover, LncRNA-TUBA4B was significantly lower expression in tumor tissues than normal lung tissues (P< 0.001). The expression of lncRNA-TUBA4B was decreased with the progression of lung cancer stage. A subgroup meta-analysis based on data resource, sample size, region, patient numbers, and tumor type was further performed. Our studies revealed that tumor tissues with low levels of TUBA4B was significantly associated with short OS, DFS, and RFS in cancer patients. Conclusion: The present findings suggest that TUBA4B can be a novel biomarker for the prognosis of various cancers.

Enhancing miR-132 expression by aryl hydrocarbon receptor attenuates tumorigenesis associated with chronic colitis

BackgroundChronic inflammation in ulcerative colitis (UC) patients is the major risk factor for colitis-associated colon cancer (CAC). Recent evidences have shown that microRNAs (miRNAs) are implicated in CAC pathogenesis. However, the interaction of miRNAs with the transcription factors that alleviate CAC has not been reported. Methods2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3′-diindolylmethane (DIM) were used to activate aryl hydrocarbon receptor (Ahr) in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC in mice. Real-time PCR was used to quantify the mRNAs of miRNA and coding genes while western blot and ELISA were used to quantify protein levels. Silencing miRNA was carried out by means of electroporation and locked nucleic acid (LNA)-miRNA. ResultsInducing CAC in mice upregulated miR-132 expression in the colon, spleen and lymph nodes at all stages of disease development. Activation of Ahr by TCDD or DIM boosted miR-132 expression and alleviated CAC severity by suppression of macrophage infiltration and pro-inflammatory cytokines. Interestingly, TCDD, but not DIM, augmented a cholinergic anti-inflammation by inducing acetylcholinesterase (AChE)-targeting miR-132. This anti-inflammation was manifested by suppressed production of TNF-α, IL-1β and IL-6. Silencing miR-132 in vivo in TCDD-treated mice abrogated the cholinergic anti-inflammation and exacerbated CAC. In addition, inhibition of miR-132 in vitro in CD4+ cells and macrophages mitigated the inhibitory effect of TCDD on AChE catalytic activity. ConclusionOur findings identify miR-132 as a new molecule implicated in CAC pathogenesis, and reveal that miR-132 mediates the ameliorating effects of TCDD on CAC, suggesting miR-132 as a promising therapeutic candidate to control autoimmune inflammation and tumorigenesis in CAC patients.

Exposure to Anisakis extracts can induce inflammation on in vitro cultured human colonic cells.

Anisakis spp. is a parasitic nematode whose infective third-stage larvae may be found within the flesh of fish species commonly consumed by humans. Thorough cooking or freezing should render the fish safe for consumption; furthermore, marinating solutions containing biocidal agents might have a significant action against Anisakis larvae. Some studies suggest a relationship between some parasitic infections and development of inflammatory bowel disorders, and Anisakis infection might be a risk factor for stomach or colon cancer. The aim of our study was to investigate if crude extracts (CEs) obtained from Anisakis larvae marinated in a solution with added allyl isothiocyanate (ACE-AITC) and frozen, or from frozen only Anisakis larvae (ACE), can induce an inflammatory effect on in vitro differentiated colonic Caco-2 cells exposed or not to LPS. Caco-2 exposure to the two CEs induced a marked COX-2 expression and potentiated LPS-induced COX-2 overexpression, confirming that substances present in Anisakis larvae can induce an inflammatory response in the intestinal epithelium, possibly also exacerbating the effects of other inflammatory stimuli. ACE induced a marked decrease in caspase-3 activation, while AITC-ACE increased its activation. However, LPS-induced caspase-3 activation appeared lower in cells treated with ACE and with the lower concentration of AITC-ACE. Thus, it is evident that Anisakis CEs may affect various cell pathways crucial not only in the inflammatory process but also in cell growth and death. Thus, CEs obtained from nonviable Anisakis larvae retain or are otherwise provided with noxious properties able to induce a strong inflammation response in intestinal epithelial cells. Furthermore, their influence may persist also following pretreatment with the biocidal agent AITC, indicating that the harmful substances contained in crude extracts from Anisakis larvae are resistant to the thermal or biocidal agent treatments.

Abstract 3220: Small molecules related to adrenomedullin reduce tumor burden in a mouse model of colitis-associated colon cancer

Abstract Adrenomedullin (AM) expression is elevated in colon cancer patients and a correlation between higher AM levels and lower disease-free survival has been described in Japan. Nevertheless, the influence of AM in colon cancer is somewhat controversial: on the one hand, antibodies against either the peptide or the receptor reduce the growth of xenografted tumors, whereas application of the peptide clearly reduces inflammation and clinical severity in human and mouse models of colitis, which is an important risk factor for colon cancer. To investigate the contribution of AM and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), to the progression and potential treatment of colon cancer we have studied the effects of several small molecules (SM) related to AM and PAMP on a mouse model of colon cancer. Colon tumors were induced by intraperitoneal injection of a carcinogen: 10 mg/Kg azoxymethane, followed by 3 cycles of a colitis-inducing chemical: 2.5% dextran sulfate sodium (DSS) in the drinking water for a week followed by 2 weeks of regular water. Four SM were tested: 16311 (a negative modulator of AM), 145425 (a positive modulator of AM), 87877 (a negative modulator of PAMP), and 106221 (a positive modulator of PAMP). For each SM, 4 experimental groups of male C57BL6 mice were used: i) Control group (injected with vehicle and drank regular water); ii) Control+SM (vehicle, regular water, and injected with the SM 3 times a week at a concentration of 20 nm/Kg); iii) Cancer group (injected with AOM and drank DSS); and iv) Cancer+SM (treated with AOM, DSS, and the SM). At the end of the experimental procedures, animals were sacrificed and the colon was extracted and analyzed. None of the mice belonging to groups i and ii developed any tumor or had any pathological finding, indicating that the SMs do not present overt toxicity. All mice in groups iii and iv developed colon neoplasias ranging from carcinomas in situ to adenocarcinomas. No significant differences were found among mice treated with PAMP modulators indicating that PAMP may not play a major role in colon cancer or that the PAMP-related SMs were not very effective. On the other hand, mice that received SM 16311 had a higher severity index (p&amp;lt;0.001) and weight loss (p&amp;lt;0.05) than their control counterparts, whereas mice injected with SM 145425 had a lower number of tumors than their controls (p&amp;lt;0.001). These results suggest that AM may have a protective role during the progression phase of colon cancer, and that treatment with AM or with positive modulator SMs may represent a novel treatment for colon cancer. This study was funded by Instituto de Salud Carlos III (PI13/02166), FEDER, and Junta Provincial de La Rioja de la Asociación Española Contra el Cáncer (AECC). Citation Format: Laura Ochoa-Callejero, Josune García-Sanmartín, Sonia Martínez-Herrero, Susana Rubio-Mediavilla, Alfredo Martínez. Small molecules related to adrenomedullin reduce tumor burden in a mouse model of colitis-associated colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3220. doi:10.1158/1538-7445.AM2017-3220

Aberrant crypt formation accompanies an increase of opportunistic pathogens/bacteria in the inflammatory gut of C57BL/6 mice fed a high‐fat diet

Obesity and high fat diet are risk factors for colon cancer, but the mechanism of this relationship remains to be determined. We tested the hypothesis that a high fat diet promotes the formation of aberrant crypt foci (ACF, preneoplastic lesions) in a manner associated with changes in hindgut bacterial taxa. We examined the susceptibility to azoxymethane (AOM)‐induced colonic ACF and microbiome composition in C57/BL6 mice fed a low fat (LF, 10% energy fat) diet or a high fat (HF, 45% energy fat) diet for 11 weeks. Mice receiving the HF diet exhibited increased plasma leptin, body weight, body fat composition and inflammatory cell infiltration in the ileum compared with those in the LF group. Consistent with a gut inflammatory phenotype, we observed an increase in colonic ACF, plasma interleukin 6 (IL6), tumor necrosis factor α (TNF α), monocyte chemoattractant protein 1 (MCP1), and inducible nitric oxide synthase protein in the ileum of the HF‐AOM group compared with those in the LF‐AOM group. Fecal DNA was extracted and 16S universal eubacterial primers were utilized to determine the microbiome composition using an amplicon pyrosequencing method. Although the HF and LF groups did not differ in bacterial alpha‐diversity, the HF and LF diets resulted in unique bacterial community structures in the hindgut. When treated with AOM, the abundance of certain short chain fatty acid (SCFA) producing bacteria (e.g., Barnesiella) and the amount of fecal SCFA (e.g., acetic acid) were lower in the HF group compared with those in the LF group. Furthermore, we identified a high abundance of Anaeroplasma bacteria (opportunistic pathogens), accompanied with ACF formation in the HF group. Taken together, we demonstrate that HF feeding promotes ACF formation associated with an increase of opportunistic pathogens / bacteria in the hindgut of C57BL/6 mice.Support or Funding InformationThis work was funded by the US Department of Agriculture, Agricultural Research Service, Research Project 3062‐51000‐050‐00D.

Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils.

Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2α in colon tumors; however, the function of epithelial HIF-2α as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2α was essential in tumor growth. Concurrently, epithelial disruption of HIF-2α significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2α-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2α signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2α-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2α-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2α-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2α is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer.

Obesity risk awareness in women with endometrial cancer.

To assess whether women with endometrial cancer could accurately classify their weight and identify the association between obesity and risk of endometrial, breast, and colon cancers. This was an IRB-approved (Project No. 14-0075), survey-based cross-sectional study of women ages 18-80years with a diagnosis of endometrial cancer. Patients were at least 6months from hysterectomy and 3months from chemotherapy or radiation. Statistical analysis was completed using Fisher's exact test, T test, ANOVA, Wilcoxon rank-sum test, or Kruskal-Wallis test. P values were two-tailed with P < 0.05 considered statistically significant. 140 women met inclusion criteria, and 133 questionnaires (95.0%) were completed. Mean age was 63.2years (range 35-80), and mean BMI was 33.4kg/m2 (range 17.6-72.2). Patients were primarily Caucasian (88.7%) and reported education beyond high school (67.8%). Among women with BMI 30.0-34.99kg/m2, 12.9% perceived themselves as obese, compared to 32.0% of women with BMI 35.0-39.99kg/m2, and 72.7% of women with BMI >40.0kg/m2. Ability to correctly classify weight correlated significantly with education level (P = 0.02). Less than half of women identified obesity as a risk factor for breast (49.6%), colon (48.1%), and endometrial cancer (44.4%). 77% of all patients had discussed weight with their primary care doctor, and 38% had discussed weight with their oncologist (P < 0.001). The majority of obese women with endometrial cancer surveyed were unable to accurately classify their weight. Given the inconsistency between patient weight and perception of cancer risk, this represents an opportunity for gynecologic oncologists to educate their patients about weight control.

Abstract A31: Biological effects of lutein and kale on the prevention of colonic inflammation and carcinogenesis

Abstract Ulcerative colitis is a risk factor for colon cancer. Dietary lutein, a nutrient rich in kale, is inversely associated with the risk of developing colon cancer in human observational epidemiologic studies. Besides lutein, kale also contains abundant amounts of other bioactive components with anti-inflammatory, antioxidant, and anti-cancer properties. As a whole food approach, kale may provide more favorable biologic effects on colonic inflammation and neoplasia than lutein alone. Additionally, it is unclear if lutein prevents colon neoplasia via the inhibition of colonic inflammation. Using a dextran sulfate sodium (DSS)-induced colitis and neoplasia mouse model, we evaluated the effects of dietary lutein supplementation and kale on the DSS-induced colorectal inflammation, ulceration, hyperplasia, dysplasia and cancer. Two hundred sixty four 8-week old Swiss-Webster (CFW) mice were assigned to one of ten groups (n = 26 to 27 in each group [13 males and 13 to 14 females]) for 21 weeks as follows: 1) 0.0005% of lutein plus DSS; 2) 0.001% of lutein plus DSS; 3) 0.002% of lutein plus DSS; 4) 0.005% of lutein plus DSS; 5) kale equivalent to 0.0005% of lutein plus DSS; 6) kale equivalent to 0.001% of lutein plus DSS; 7) kale equivalent to 0.002% of lutein plus DSS; 8) kale equivalent to 0.005% of lutein plus DSS; 9) DSS only; and 10) control with no treatment. During the 21-week experimental period, mouse body weights were recorded weekly. At week 7, the mice in groups 1-9 were given DSS for 4 cycles (1 cycle = 1 week 3% of DSS in drinking water followed by 2-week water) to induce colitis and colorectal neoplasia. This report described the findings on the presence of clinical signs of colitis (hemoccult and loose stools, which were evaluated at the end of each week throughout the experiments), and the findings from histopathological evaluations (inflammation, ulceration, hyperplasia, dysplasia, and neoplasia). Dietary lutein and kale, particularly two higher doses (0.002% and 0.005%), reduced the DSS-induced hemoccult and loose stools, as well as the DSS-induced inflammation, ulceration, hyperplasia, dysplasia, and neoplasia. These data suggest that dietary lutein and kale may prevent the DSS-induced colorectal inflammation and associated preneoplastic and neoplastic lesions. Grant Funding Sources: This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2014-67017-21754 from the USDA National Institute of Food and Agriculture and by USDA/ARS grant 1950-51000-074S. Citation Format: Chun Liu, Roderick T. Bronson, Xiang-Dong Wang. Biological effects of lutein and kale on the prevention of colonic inflammation and carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A31.

Knowledge Attitude and Practice of Colorectal Cancer among School Teachers in Al-Ahsa Saudi Arabia

Background:Colorectal cancer is the second leading cause of deaths among cancers affecting both men and women in the United States. Annually, about 140,000 Americans are diagnosed with colorectal cancer, and more than 50,000 people die from it. In Saudi Arabia, this cancer ranks first among men and third among women. Nevertheless, this type of cancer is one of the most preventable types of cancer.Objective:The aim of this study was to assess the level of colorectal cancer awareness among teaching staff (educators) in Al-Ahsa, Saudi Arabia.Methodology:The current cross-sectional study was conducted in teaching staff in Al-Ahsa, Eastern province, Saudi Arabia, from February 2017 to May 2017. A self-administered questionnaire was used for data collection and SPSS (version 24) was run for data analysis.Result:A total of 367 teachers (165 males and 202 females) were recruited for the present investigation. The participants aged from 25 to 55 years and most of them were married (87%). The majority had inadequate knowledge about risk factors of colon cancer. No significant difference was observed between people living in urban and rural areas regarding knowledge of risk factors for colorectal cancer (p≥0.05). Concerning colorectal cancer screening tests, 39% of men and 42% of women were unaware; although, 12.8% of the participants reported a positive family history of colon cancer. In General, participants with higher education level had higher level of awareness on colon cancer.Conclusions:The findings of this study demonstrated that most of educators, including men and women are unaware of colon cancer risk factor. Furthermore, their knowledge of colon cancer signs, symptoms, and screening methods were inadequate. With respect to our findings, enhancement of colon cancer knowledge among educators is recommended using health education campaign in Al-Ahsa.

N-acetyl transferase 2/environmental factors and their association as a modulating risk factor for sporadic colon and rectal cancer.

The aim of this study was to evaluate the association between environmental factors and colon or rectal cancer after adjusting for N-acetyl transferase 2 (NAT2) phenotypes. Ninety-six patients with sporadic colon cancer, 54 with sporadic rectal cancer and 162 control subjects were genotyped for NAT2-T341C, G590A, G857A, A845C, and C481T using sequencing and PCR-RFLP analysis. The risk for colon cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, and NAT2*5A-C481T. The risk for rectal cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*7B-G857A, and NAT2*5A-C481T. High fried red meat intake associated with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele determines a risk of 2.39 (P=.002), 2.39 (P=.002), 2.37 (P=.002), 2.28 (P=.004), and 2.51 (P=.001), respectively, for colon cancer, whereas in the case of rectal cancer, the risk increased to 7.55 (P<.001), 7.7 (P<.001), 7.83 (P<.001), 7.51 (P<.001), and 8.62 (P<.001), respectively. Alcohol consumption associated with the NAT2 -T341C, G590A, G857A, A845C, and C481T rapid acetylator allele induces a risk of 10.63 (P<.001), 12.04 (P<.001), 9.76 (P<.001), 10.25 (P<.001), and 9.54 (P<.001), respectively, for colon cancer, whereas the risk for rectal cancer is 9.72 (P<.001), 11.24 (P<.001), 13.07 (P<.001), 10.04 (P<.001), and 9.43 (P<.001), respectively. Smokers with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele have a risk of 4.87, 4.25, 4.18, 3.81, and 3.82, respectively, to develop colon cancer. Fried red meat, alcohol, and smoking increase the risk of sporadic CRC, especially of colon cancer, in the case of rapid acetylators for the NAT2 variants.

Impact of Increased Visceral Fat Measured by CT on Colon Adenocarcinoma Stage.

Obesity is considered a risk factor for colon cancer. Worse outcome observed in colon cancer patients with obesity may have several mechanisms. However, the influence of obesity on colon cancer stage is yet to be clarified. The objective of this study was to determine the relationship between obesity and stage on presentation. This is a retrospective analysis of patients' files in one university affiliated medical center. Included in this study were non-metastatic patients who underwent colectomy for adenocarcinoma of the colon in whom both the preoperative abdominal computed tomography and the postoperative pathology report were available for evaluation. Abdominal computed tomography measurement of retroperitoneal fat thickness was used as an indicator of obesity. Data was analyzed according to quartiles of fat thickness. Of 83 patients, 38 were males and 45 were females. Median age was 71years (range 43-90years). Increased retroperitoneal fat thickness was not associated with advanced T and N stages on presentation. Rather, patients in the first quartile presented with the worst T and N stages. The proportion of patients with T3 and T4 tumors was 95, 76.2, 66.7, and 66.7% in quartiles 1, 2, 3, and 4, respectively (p=0.0327), while the proportion of patients with positive lymph node metastasis was 60, 23.8, 23.8, and 42.9% in quartiles 1, 2, 3, and 4, respectively (p=0.0319). The data presented here does not support the association of obesity with worse stage at presentation of colon cancer, and other possible mechanisms for worse outcome should be sought.