Severity Of Colorectal Cancer Research Articles

Structural Basis of the Inhibition of L-Methionine γ-Lyase from Fusobacterium nucleatum.

Fusobacterium nucleatum is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (FN0625, FN1055, FN1220, and FN1419) of F. nucleatum are involved in producing hydrogen sulfide (H2S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 Å, showing the unique conformation of the PLP-binding site when compared with L-methionine γ-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H2S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5'-phosphate-binding site. Gallic acid has little effect on the other H2S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from F. nucleatum and found a new lead compound for inhibitor development.

Protective Role of IL7A-197 A/G Heterozygosity in the Development and Severity of Colorectal Cancer in the Bulgarian Population.

Background: Interleukin (IL)-17A and IL-17F, expressed mainly by a novel subset of CD-positive (+) T-helper (Th) cells of the immune system, has been closely related to inflammatory conditions underlying colorectal cancer pathogenesis. Accordingly, we conducted a case-control study to investigate the association of common single nucleotide polymorphisms (SNP) in the IL17A and IL17F genes (rs2275913 and rs763780, respectively) with the susceptibility and severity of CRC patients from the Bulgarian population. Methods and Materials: 136 patients with histologically confirmed CRC diagnosis and 116 healthy individuals were recruited in the present study. Genotypes were determined by the restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) technique. Results: The IL17A heterozygous A/G-genotype was overrepresented among the control group (p = 0.003). Additionally, the carriers of the heterozygous A/G-genotype had a 2.39-fold lower risk for CRC compared to the G/G-genotype (OR = 0.418, p = 0.006). Our results also indicated that in the advanced CRC stages (III + IV) the heterozygous genotype (A/G) appeared to be less frequent (p = 0.024, χ2-test). Among the patients with detected distant metastases, the A/G-carriers were the smallest part (14.3%) compared to the homozygous genotypes A/A (42.9%) and G/G (42.8%), p = 0.006. There was no association of the studied IL17F rs763780 SNP with susceptibility and severity of CRC among the studied subjects, although the heterozygous C/T-carriers had shorter median survival compared to the T/T-carriers (p = 0.129). Conclusions: Our study finds a protective role of heterozygosity for the IL17A-197A/G SNP and negative effects of the A-allele on CRC progression.

Prognostic value of combining E-cadherin, p53, Bcl-2 and Bcl-xL expression and survival in Tunisian colorectal adenocarcinoma patients.

Colorectal cancer (CRC) is a commonhealth issue worldwide with an extremely low survival rate after relapse. This study aims to evaluate the immunohistochemical expression of p53, E-cadherin, Bcl-2 and Bcl-xL and find a potential correlation between these markers, clinicopathological factors and overall survival of colorectal cancer patients. Marker expression was immunohistochemically determined in 105 patients with colorectal adenocarcinoma from southern Tunisia, followed by statistical analysis. Positivity rate of nuclear p53, membranous E-cadherin and cytoplasmic Bcl-2 - Bcl-xL was 85.71%, 76.47%, 59.8%, and 85.71% respectively. Spearman correlation showed that p53 was significantly and positively related to E-cadherin, Bcl-2, Bcl-xL and distant metastasis. A positive significant correlation between E-cadherin and anti-apoptotic proteins was also seen. Membranous E-cadherin expression was significantly and negatively associated to poor prognosis factors including lymph node metastasis, lymph invasion, venous invasion and distant metastasis. Bcl-2 expression was significantly correlated to distant metastasis. Multivariate analysis showed a significant association between dependent variable E-cadherin and covariates including differentiation, lymph invasion, venous invasion, distant metastasis, Bcl-2 and Bcl-xL. Poor 3-years OS and 5-years OS were significantly related to p53, Bcl-2 expression and E-cadherin loss. Positive E-cadherin combined with negative p53 and Bcl-2 as well as double-positive for E-cadherin and Bcl-xL were associated to best overall survival. Although each protein can be an independent prognostic factor, Simultaneous E-cadherin, p53, Bcl-2, Bcl-xL expression could be a crucial prognostic and overall survival marker to CRC patients. Multivariate analysis confirmed a positive correlation between membranous E-cadherin loss and colorectal cancer severity.

Regulation of gene expression in the development of colitis-associated colon cancer in mice fed a high-fat diet

Studies have shown that the higher prevalence of colorectal cancers among patients with inflammatory bowel disease. Thus, proinflammatory stimulus due to a high-fat diet may impose a higher risk on the development of colorectal cancer. In the present study, we applied a transcriptomic approach to characterize the molecular mechanism(s) by which high-fat feeding aggravates colitis-associated colorectal cancer (CAC). A high-fat diet was supplied in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model for 10 weeks and then the severity of CAC and global gene expression in colon were assessed. Although consumption of high-fat diet did not significantly aggravate CAC, it substantially changed gene expression profile in colon. In AOM/DSS treated mice (AD group) and AD mice fed a high-fat diet (AD + HF group), 34 and 54 DEGs were enriched in ‘pathways in cancer’, respectively. Notably, high-fat diet upregulated the expression of genes associated with spliceosome and ribosome biogenesis, and downregulated the expression of genes associated with lipid catabolism in mice treated with AOM/DSS. In addition, we identified that DEGs between the AD and AD + HF groups, were enriched in ‘metabolic pathways’, especially amino acid and nucleotide metabolism. Taken together, this study provides the molecular mechanism in understanding the high-fat diet-mediated CAC development.

Methanolic Extract of Muntingia Calabura L. Mitigates 1,2-Dimethyl Hydrazine Induced Colon Carcinogenesis in Wistar Rats

Objective The present study aimed to evaluate the efficacy of methanolic extract of Muntingia calabura L. leaves (MEMC) in ameliorating oxidative stress and inflammation associated with 1,2-dimethyl hydrazine (DMH) induced colon cancer. Methods The antioxidant enzymes, oxidative stress markers, liver and renal toxicity markers were evaluated. Histopathological examination of colon tissues was carried out with the aid of alcian blue stain and Hematoxylin and Eosin stain. Results MEMC supplementation at doses of 100 and 200 mg/kg body weight of rats causes the antioxidant enzymic levels to retain near to its normal range. Meanwhile the oxidative stress markers, which showed an elevation from its normal level upon DMH administration, gets significantly reduced on MEMC treatment. Histopathological observation also revealed that the severity of colorectal cancer was reduced by the supplementation of MEMC. Conclusion The findings from the present study showed that MEMC can exert a potential role to ameliorate the oxidative stress and inflammation associated with colorectal cancer.

Utilizing Whole Fusobacterium Genomes To Identify, Correct, and Characterize Potential Virulence Protein Families.

Fusobacterium spp. are Gram-negative, anaerobic, opportunistic pathogens involved in multiple diseases, including a link between the oral pathogen Fusobacterium nucleatum and the progression and severity of colorectal cancer. The identification and characterization of virulence factors in the genus Fusobacterium has been greatly hindered by a lack of properly assembled and annotated genomes. Using newly completed genomes from nine strains and seven species of Fusobacterium, we report the identification and corrected annotation of verified and potential virulence factors from the type 5 secreted autotransporter, FadA, and MORN2 protein families, with a focus on the genetically tractable strain F. nucleatum subsp. nucleatum ATCC 23726 and type strain F. nucleatum subsp. nucleatum ATCC 25586. Within the autotransporters, we used sequence similarity networks to identify protein subsets and show a clear differentiation between the prediction of outer membrane adhesins, serine proteases, and proteins with unknown function. These data have identified unique subsets of type 5a autotransporters, which are key proteins associated with virulence in F. nucleatum However, we coupled our bioinformatic data with bacterial binding assays to show that a predicted weakly invasive strain of F. necrophorum that lacks a Fap2 autotransporter adhesin strongly binds human colonocytes. These analyses confirm a gap in our understanding of how autotransporters, MORN2 domain proteins, and FadA adhesins contribute to host interactions and invasion. In summary, we identify candidate virulence genes in Fusobacterium, and caution that experimental validation of host-microbe interactions should complement bioinformatic predictions to increase our understanding of virulence protein contributions in Fusobacterium infections and disease.IMPORTANCEFusobacterium spp. are emerging pathogens that contribute to mammalian and human diseases, including colorectal cancer. Despite a validated connection with disease, few proteins have been characterized that define a direct molecular mechanism for Fusobacterium pathogenesis. We report a comprehensive examination of virulence-associated protein families in multiple Fusobacterium species and show that complete genomes facilitate the correction and identification of multiple, large type 5a secreted autotransporter genes in previously misannotated or fragmented genomes. In addition, we use protein sequence similarity networks and human cell interaction experiments to show that previously predicted noninvasive strains can indeed bind to and potentially invade human cells and that this could be due to the expansion of specific virulence proteins that drive Fusobacterium infections and disease.

Health belief of colorectal cancer in relatives of patients with hereditary colorectal cancer and its influencing factors

Objective To investigate the health belief of colorectal cancer and its screening in relatives of patients with hereditary colorectal cancer, and to analyze its influencing factors. Methods Totally 148 blood relatives of patients with hereditary colorectal cancer hospitalized in the Department of Colorectum of a Class Ⅲ Grade A hospital in Guangzhou from December 2016 to May 2018 were selected using convenient sampling, and investigated with the self-made general information questionnaire and Chinese Colorectal Cancer Health Belief Scale (CCCHBS) . SPSS 20.0 was used for statistical analysis. Results The colorectal cancer health belief of blood relatives of patients with hereditary colorectal cancer totaled (3.37±0.35) in which the perception and acceptance levels of screening benefits, health motives and self-efficacy of colorectal cancer were higher, while the perception levels of severity of colorectal cancer, barriers against colorectal screening and susceptibility were lower. Multivariate linear regression analysis revealed that household income per capita, educational background, with commercial medical insurance or not and the number of blood relatives with cancer were the influencing factors for health belief levels, which accounted for 41.9% of the total variance. Conclusions The health belief in blood relatives of patients with hereditary colorectal cancer remain at a medium level. Medical and nursing workers should pay attention to the blood relatives of patients with hereditary colorectal cancer with lower educational background, lower household income and less blood relatives with cancer, take measures to improve their health belief levels, and facilitate colorectal cancer screening behaviors so as to prevent and control colorectal cancer in a better manner. Key words: Colorectal neoplasms; Health attitude; Hereditary; Blood relatives; Health belief

Differential susceptibility to colorectal cancer due to naturally occurring gut microbiota.

Recent studies investigating the human microbiome have identified particular bacterial species that correlate with the presence of colorectal cancer. To evaluate the role of qualitatively different but naturally occurring gut microbiota and the relationship with colorectal cancer development, genetically identical embryos from the Polyposis in Rat Colon (Pirc) rat model of colorectal cancer were transferred into recipients of three different genetic backgrounds (F344/NHsd, LEW/SsNHsd, and Crl:SD). Tumor development in the pups was tracked longitudinally via colonoscopy, and end-stage tumor burden was determined. To confirm vertical transmission and identify associations between the gut microbiota and disease phenotype, the fecal microbiota was characterized in recipient dams 24 hours pre-partum, and in Pirc rat offspring prior to and during disease progression. Our data show that the gut microbiota varies between rat strains, with LEW/SsNHsd having a greater relative abundance of the bacteria Prevotella copri. The mature gut microbiota of pups resembled the profile of their dams, indicating that the dam is the primary determinant of the developing microbiota. Both male and female F344-Pirc rats harboring the Lewis microbiota had decreased tumor burden relative to genetically identical rats harboring F344 or SD microbiota. Significant negative correlations were detected between tumor burden and the relative abundance of specific taxa from samples taken at weaning and shortly thereafter, prior to observable adenoma development. Notably, this naturally occurring variation in the gut microbiota is associated with a significant difference in severity of colorectal cancer, and the abundance of certain taxa is associated with decreased tumor burden.

Colorectal cancer severity and survival in correlation with tumour necrosis factor-alpha

Colorectal cancer (CRC) development is strongly associated with innate immune mechanisms and intestinal inflammation. The aim of the study was to investigate the pre-operative serum levels of TNF-α and its correlation with cancer progression and survival in CRC patients taking into account the genotype of –308G/A promoter polymorphism in TNF-α gene (rs1800629). TNF-α –308G/A genotypes of 119 CRC cases and 177 no CRC controls were determined by restriction fragment length polymorphism assay (RFLP-PCR). TNF-α serum levels were measured by enzyme-linked immunosorbent assay (ELISA). Although no significant differences in allele and genotype frequencies between CRC and controls were observed, it should be noted that the minor allele-A and its homozygous genotype were overrepresented among CRC. In addition, allele-A was more frequent in early CRC patients compared to advanced cases. TNF-α serum level was significantly higher in CRC patients than in controls (36.1 ± 8.4 pg/mL vs. 18.66 ± 11 pg/mL; p = 0.0000001). In the subgroup analysis by tumour–node–metastasis stages, the highest TNF-α level was found in stage IV (42.7 ± 12.5 pg/mL) and was significantly elevated compared to earlier stages of CRC and controls. The survival rate of CRC patients with low TNF-α serum level, estimated as median survival, was significantly higher than that of patients with high levels of TNF-α (38.4 vs. 7.761 months; log rank test p = 0.00015) In conclusion, we can affirm that TNF-α affects tumour development along with disease progression which has an impact on the survival of CRC.

Abstract 5256: Gender bias in rat models of colorectal cancer is owing to male hormone promotion, not female hormone protection

Abstract Several large human colonoscopy screening cohort studies have found a significant sex and age-specific prevalence of advanced adenomas and colorectal cancer in males, with females showing a delayed onset and decreased incidence of advanced lesions. It has been postulated that women are protected from colorectal cancer owing to a protective effect of estrogen and progesterone, or that males are exposed to higher levels of environmental toxins. We find in both a genetic and a carcinogen-induced model of colorectal cancer in rats that male hormones are responsible for the male-specific enhancement of colon cancer. We have reported that the Polyposis in the rat colon (Pirc) rat shows a strong gender bias, with females having a later onset and reduced tumor burden compared to males. We have next investigated the role of hormones through ovariectomy and hormone replacement in female rats. F344-Pirc rat litters were divided and either underwent surgical ovariectomy or sham ovariectomy between 35 and 40 days of age. At the time of surgery, females received subcutaneous slow release (90 day) pellets with the following treatments: placebo; 17-beta estradiol (E2); medroxypregesterone (MPA); or a combination of E2 and MPA, renewed after 90 days, and sacrificed 180 days post ovariectomy. The controls were cohorts of females that did not receive surgical treatment (n=10), and sham ovariectomized females (n=10). Females that underwent ovariectomy and received either E2 (n=10) or the combination of E2 and MPA (n=10) had reduced body weight and were observed to be much leaner than animals treated with MPA alone (n=10, p=0.006) or placebo (n=8, p=0.005). Importantly, tumor multiplicities did not significantly differ among all female groups, but were significantly lower than those observed in intact males (n=32, mean 39.4, p=4.7e-14). We postulated that the difference of tumor susceptibility between sexes is due to the effect of male hormones. At weaning (30-35 days) half of the F344-Pirc males underwent orchidectomy. Males that underwent castration (n=16) had a significantly lower tumor multiplicity (mean=16.9) compared to all other males (n=32, mean= 39.4, p=1.3e-6). Males that underwent castration were indisguishable from all Pirc female cohorts, treated or not, strongly suggesting that male gonadal hormones are the significant hormones controlling the multiplicity of colonic adenomas. To determine if this response was specific to our genetic model, cohorts of F344 male rats either underwent orchidectomy or sham operation, and were then treated with the carcinogen azoxymethane. The orchidectomized cohort had a significantly lower number of aberrant crypt foci compared to the sham treated males (p=0.01). We are testing, through DHT replacement in the Pirc rat, whether testosterone is directly promoting the earlier onset and increased severity of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5256. doi:1538-7445.AM2012-5256

The association of pretreatment health-related quality of life with surgical complications for patients undergoing open surgical resection for colorectal cancer.

The purpose of this study was to define the association between pretreatment health-related quality of life (HRQL) and surgical complications for patients with colorectal cancer. For patients with colorectal cancer, surgical complications arise from an interaction between underlying medical comorbidity, colorectal cancer severity, and quality and type of treatment provided. Measurement of HRQL provides a summarization of well-being in the context of medical comorbidity and colorectal cancer severity. The summarization of these factors may be useful in prospective risk assessment of patients about to undergo surgery for colorectal cancer. A single-institution, prospective, cohort study of patients with colorectal adenocarcinoma was performed from August 1, 1999, to March 31, 2002. Before treatment, all participants completed Medical Outcomes Survey SF-36 (SF-36); after the first year of the study, patients also completed the colorectal cancer module of the Functional Assessment of Cancer Therapy survey (FACT-C). Information was collected on demographics, treatment, tumor variables, and complications. Ninety-seven patients have undergone open resection of their colorectal cancer. All patients completed SF-36; 65 completed FACT-C. Thirty patients (31%) experienced complications, including 4 (4%) deaths. Age, race, albumin level, American Society of Anesthesia class, specialty surgical training, tumor location, and stage were not associated with complications in univariate analysis. Patients experiencing surgical complications had significantly lower HRQL scores on SF-36 Social Functioning, General Health Perception, and Mental Health Index scales as well as the Mental Health Component summary score. FACT-C Social/Family, Emotional, Functional Well-Being scores, and the Colorectal Cancer Concerns score were also significantly lower for patients sustaining complications. When these HRQL scales were examined in a multivariate model including albumin level, tumor location, and ASA class, SF-36 Social Functioning (Odds Ratio [OR] = 0.98; 95% Confidence Interval [CI] = 0.97-0.99) and FACT-C Colorectal Cancer Concerns (OR = 0.89; 95% CI = 0.79-0.99) scales retained a significant association with complications. Pretreatment HRQL scores as measured by several scales of SF-36 and FACT-C were significantly associated with complications. Future studies should concentrate on defining the predictive role of HRQL in determining surgical outcome for patients with colorectal cancer.