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Colorectal Mucosa (colorectal + mucosa)
Selected AbstractsFolate, colorectal carcinogenesis, and DNA methylation: Lessons from animal studiesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2004Young-In Kim Abstract Folate, a water-soluble B vitamin and cofactor in one-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer (CRC). Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with CRC risk. Collectively, these studies suggest an , 40% reduction in the risk of CRC in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose-dependent protective effect of folate supplementation. However, animal studies also have shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote, rather than suppress, colorectal carcinogenesis. These animal studies, in conjunction with clinical observations, suggest that folate possesses dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect, whereas folate supplementation has a promoting effect on the progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these studies suggest that the optimal timing and dose of folate intervention must be established for safe and effective chemoprevention in humans. Folate is an important factor in DNA synthesis, stability, and integrity, the repair aberrations of which have been implicated in colorectal carcinogenesis. Folate may also modulate DNA methylation, which is an important epigenetic determinant in gene expression (an inverse relationship), in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. A mechanistic understanding of how folate status modulates colorectal carcinogenesis further strengthens the case for a causal relationship and provides insight into a possible chemopreventive role of folate. Environ. Mol. Mutagen. 44:10,25, 2004. © 2004 Wiley-Liss, Inc. [source] Whole genome analysis for liver metastasis gene signatures in colorectal cancerINTERNATIONAL JOURNAL OF CANCER, Issue 9 2007Dong Hyuk Ki Abstract Liver metastasis is one of the major causes of death in colorectal cancer (CRC) patients. To understand this process, we investigated whether the gene expression profiling of matched colorectal carcinomas and liver metastases could reveal key molecular events involved in tumor progression and metastasis. We performed experiments using a cDNA microarray containing 17,104 genes with the following tissue samples: paired tissues of 25 normal colorectal mucosa, 27 primary colorectal tumors, 13 normal liver and 27 liver metastasis, and 20 primary colorectal tumors without liver metastasis. To remove the effect of normal cell contamination, we selected 4,583 organ-specific genes with a false discovery rate (FDR) of 0.0067% by comparing normal colon and liver tissues using significant analysis of microarray, and these genes were excluded from further analysis. We then identified and validated 46 liver metastasis-specific genes with an accuracy of 83.3% by comparing the expression of paired primary colorectal tumors and liver metastases using prediction analysis of microarray. The 46 selected genes contained several known oncogenes and 2 ESTs. To confirm that the results correlated with the microarray expression patterns, we performed RT-PCR with WNT5A and carbonic anhydrase II. Additionally, we observed that 21 of the 46 genes were differentially expressed (FDR = 2.27%) in primary tumors with synchronous liver metastasis compared with primary tumors without liver metastasis. We scanned the human genome using a cDNA microarray and identified 46 genes that may play an important role in the progression of liver metastasis in CRC. © 2007 Wiley-Liss, Inc. [source] Inhibition of Alcohol-Associated Colonic Hyperregeneration by ,-Tocopherol in the RatALCOHOLISM, Issue 1 2003P. Vincon Background: Chronic alcohol consumption results in colorectal mucosal hyperregeneration, a condition associated with an increased risk for colorectal cancer. Possible mechanisms may involve the effects of acetaldehyde and/or free radicals generated during alcohol metabolism. Vitamin E is part of the antioxidative defense system, and its concentration is decreased or its metabolic utilization increased in various tissues after chronic alcohol consumption. We wondered whether ,-tocopherol supplementation may prevent ethanol-induced colorectal cell cycle behavior and whether these changes were related to alterations in protein synthesis. Methods: Five groups of male Wistar rats, each consisting of 14 animals, received liquid diets as follows: group 1, alcohol; group 2, alcohol +,-tocopherol; group 3, control (i.e., isocaloric glucose); group 4; control (i.e., isocaloric glucose) +,-tocopherol. Group 5 was fed a solid chow diet ad libitum. After 4 weeks of feeding, immunohistology was performed with anti-proliferating cell nuclear antigen (PCNA) or anti-BCL2 antibodies. Fractional (ks) and absolute (Vs) rates of protein synthesis and rates of protein synthesis relative to RNA (kRNA) and DNA (kDNA) were measured with a flooding dose of L-[4- 3H] phenylalanine with complementary analysis of protein and nucleic acid composition. Results: The PCNA index was increased significantly in the colon after ethanol administration compared with controls (ethanol, 10.3 ± 2.3 vs. control, 6.51 ± 1.6% PCNA positive cells, p < 0.05), although neither the protein, RNA, and DNA concentrations nor ks, kRNA, kDNA, and Vs were affected. This increase in PCNA index was significantly diminished by coadministration of ,-tocopherol (ethanol +, - tocopherol, 7.86 ± 1.71% PCNA positive cells, p < 0.05) without significant alterations in protein synthetic parameters. A similar result was obtained for the PCNA index in the rectal mucosa (ethanol, 14.6 ± 4.4 vs. control, 12.1 ± 4.2% PCNA positive cell), although this did not reach statistical significance. Neither ethanol nor , - tocopherol feeding had any significant effect on BCL-2 expression in the colorectal mucosa. As with the colon, protein synthetic parameters in the mucosa were not affected by alcohol feeding at 4 weeks. These effects on colonic cell turnover without corresponding changes in protein synthesis thus represent a specific localized phenomenon rather than a general increase in anabolic processes in the tissue and reaffirm the hyperregenerative properties of chronic alcohol consumption. Conclusions: Alcohol-associated hyperproliferation could be prevented, at least in part, by supplementation with ,-tocopherol. This may support the hypothesis that free radicals are involved in the pathogenesis of alcohol-associated colorectal hyperproliferation. [source] The effect of unfiltered coffee on potential biomarkers for colonic cancer risk in healthy volunteers: a randomized trialALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2000Grubben Background: Epidemiologic studies suggest that coffee use might protect against colorectal cancer. Inconsistencies as to the effect of coffee use and colorectal cancer between epidemiologic studies might be related to the type of coffee brew. Objective: We studied the effect of unfiltered coffee consumption on putative biomarkers for colonic cancer risk. Design: A total of 64 healthy volunteers (31 men and 33 women), with a mean age of 43 ± 11 years were randomly assigned to two groups in a crossover design, with two intervention periods of 2 weeks separated by a washout period of 8 weeks. Treatments were 1 L of cafetière (French press) coffee daily or no coffee. At the end of each intervention period, fasting blood samples, colorectal biopsies and 48 h faeces were collected. Results: No effect of coffee on colorectal cell proliferation, assayed by estimating the Proliferating Cell Nuclear Antigen labelling index, was seen. Additionally, no effects were seen on the concentrations of faecal soluble bile acids and colorectal mucosal glutathione S-transferase activity. However, unfiltered coffee significantly increased the glutathione content in the colorectal mucosa by 8% and in plasma by 15%. Other aminothiols in plasma also increased on coffee. Conclusion: Unfiltered coffee does not influence the colorectal mucosal proliferation rate, but might increase the detoxification capacity and anti-mutagenic properties in the colorectal mucosa through an increase in glutathione concentration. Whether this effect indeed contributes to a lower colon cancer risk remains to be established. [source] Basement membrane laminin-5 is deposited in colorectal adenomas and carcinomas and serves as a ligand for ,3,1 integrinAPMIS, Issue 3 2000Jouni Lohi Interplay between laminin-5 (Ln-5) and its integrin (Int) receptors ,2,1, ,3,1 and ,6,4 has been implicated in the progression and invasion of carcinomas. In this study we found abundant immuno-reactivity for chains of Ln-5 (,3-,3-,2) and Ln-10 (,5-,1), as well as for type VII collagen, in basement membranes (BM) of colorectal adenomas. In carcinomas of all differentiation grades, Lns were seen in tumor BMs, whereas type VII collagen was almost absent. Ln-5 appeared to accumulate along the invading edges of carcinomas, while Ln-10 was mostly absent. Immunoreactivity for Ln ,1 chain, a component of Lns-1 and -3, was not seen in adenomas or carcinomas. Immunoreactivity for ,2, ,6, ,1 and ,4 Ints was found in all tumors and that for ,3 Int in all adenomas and most of the carcinomas, often in colocalization with Ln-5. Immunoblotting of carcinoma tissues showed that the ,2 chain of Ln-5 was present as typical Mr 105000 and 155000 isoforms. Immunoprecipitation experiments showed production of Ln-5 by cultured colon carcinoma cells. In quantitative cell adhesion experiments, function-blocking MAbs to ,3 and ,1 Int subunits, but not those to Int ,2 or ,6 subunits, significantly inhibited the adhesion of cells to Ln-5. Our results suggest that BM composition in colorectal adenomas reflects the properties of surface epithelial BM of colorectal mucosa. In invading carcinomas, trimeric Ln-5, produced by carcinoma cells, is a major BM component and the cells use the ,3,1 Int complex for adhesion to Ln-5. [source] Genetic and epigenetic changes in aberrant crypt foci and serrated polypsCANCER SCIENCE, Issue 6 2008Yutaka Suehiro Aberrant crypt foci (ACF) in colorectal mucosa are the earliest known morphological precursors to colorectal cancer and can be subclassified as dysplastic, heteroplastic (non-dysplastic), and mixed types. Serrated adenoma (SA) is a polyp with serrated architecture and dysplasia, and can be subclassified as traditional SA or sessile SA. Sessile SA is thought to be preneoplastic and differs from most lesions in the traditional SA category because of their flat morphology and general lack of cytological dysplasia. Serrated polyps include hyperplastic polyps (HP), SA, and admixed hyperplastic-adenomatous polyps and are considered a morphological continuum encompassing heteroplastic ACF, HP, admixed hyperplastic-adenomatous polyps, and SA. Recent studies have uncovered other developmental pathways including a heteroplastic ACF-HP/SA-carcinoma sequence and a heteroplastic ACF,adenoma,carcinoma sequence. Heteroplastic ACF histopathologically resemble HP and SA. Sporadic HP are usually present in the left colon, are small, and are considered benign. However, adenocarcinoma arising in the setting of colorectal HP or SA, especially in patients with hyperplastic polyposis, has been described. The relationship between heteroplastic ACF, HP, and colorectal cancer is less certain than that of dysplastic ACF. Here, we discuss the current understanding of genetic and epigenetic alterations in the development of colorectal cancer. Our goal is to provide a conceptual framework for understanding the heteroplastic ACF,HP/SA,carcinoma sequence. (Cancer Sci 2008; 99: 1071,1076) [source] Enhanced Formation of Azoxymethane-induced Colorectal Adenocarcinoma in ,, T Lymphocyte-deficient MiceCANCER SCIENCE, Issue 8 2001Shunji Matsuda T cell receptor (TCR) ,, -positive T lymphocytes, which are localized mostly within the intraepithe-lial space of intestinal epithelium, have been suggested to play a role in maintaining the normal configuration of intestinal epithelium. However, the role of TCR,, -positive T lymphocytes in the formation and progression of colorectal adenocarcinoma that originates from colorectal epithelial cells remains to be elucidated. In this study, TCR,, and TCR,, -positive T lymphocyte-deficient mice (homozygous TCR, and TCR,-gene knockout mice) and the background wild-type mice were administered azoxymethane, and the formation of macroscopic tumors and microscopic aberrant crypt foci in colorectal mucosa were compared among the three types of mice. Well-differentiated adenocarcinoma appeared 5 months after 5 administrations of azoxymethane (10 mg/kg weight) only in a few TCR,-gene knockout mice and the frequency of the carcinoma-bearing mice was increased at 7 and 9 months after the administration. Aberrant crypt foci were also detected in the colorectal mucosa of TCR,-gene knockout mice to a greater extent than in colorectal mucosa of TCR,-gene knockout mice 1 month after the azoxymethane administration. These results suggest that TCR,, -positive T lymphocytes, which are present mainly in the intraepithelial space, play a role in suppression of the formation and progression of colorectal adenocarcinoma in mice. 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