Studies Of Colon Carcinogenesis Research Articles

Enhancement of colon carcinogenesis by the combination of indole-3 carbinol and synbiotics in hemin-fed rats

The risk of developing colorectal cancer (CRC) could be associated with red and processed meat intake. Experimental data supports that hemin iron, found abundantly in red meat, promotes CRC in mice and rats, while indole-3 carbinol (I3C) and synbiotics (syn) exert anti-carcinogenic activities in most studies of colon carcinogenesis. This study aimed to investigate the modifying effects of I3C and syn (inulin + Bifidobacterium lactis), given separately or together, on dimethylhidrazine (DMH)-induced colon carcinogenesis in hemin-fed rats. All animals were given four subcutaneous DMH injections and then, two weeks after carcinogen exposure, they began a basal diet containing hemin, hemin + I3C, hemin + syn, or hemin + I3C + syn for 23 weeks. The combination of I3C + syn significantly increased fecal water genotoxicity, tumor volume and invasiveness when compared to the hemin-fed control group. The groups fed I3C or syn alone had a significant reduction in the number of preneoplastic aberrant crypt foci (ACF) lesions compared to the hemin-fed group. Dietary I3C also reduced fecal water genotoxicity. Gene expression analysis of colorectal tumors demonstrated that the combination of dietary I3C + syn increased transcript levels for Raf1 and decreased tumor progression and invasiveness related to the genes Cdh1 and Appl1. This analysis also revealed that the Tnf and Cdh1 genes were significantly up- and down-regulated, respectively, in tumors of rats that received I3C, in comparison with the hemin-fed group. These findings reveal that the joint administration of I3C and syn enhanced the development of colon tumors induced by DMH in hemin-fed rats, while they potentially reduced ACF development when given alone.

Genotoxic potential and in vitro tumour-promoting potential of 2-dodecylcyclobutanone and 2-tetradecylcyclobutanone, two radiolytic products of fatty acids

The DNA-damaging and tumour-promoting effects of two 2-alkylcyclobutanones (2-ACBs), which are found in irradiated fat-containing foods, were investigated by use of the comet assay and in an azoxymethane (AOM)-induced colon-carcinogenesis study in rats, respectively. We conducted genotoxicity tests of 2-dodecylcyclobutanone (2-dDCB) and 2-tetradecylcyclobutanone (2-tDCB) according to the test guidelines for chemicals or drugs. In addition, a cell-transformation assay with Bhas 42 cells was performed to investigate their promoting potential in vitro.The Salmonella typhimurium mutagenicity assay (Ames test), conducted with five tester strains, revealed that neither 2-dDCB nor 2-tDCB possessed mutagenic activity. Moreover, both in the in vitro chromosomal aberration test on CHL/IU cells and the in vivo bone-marrow micronucleus test where mice were given 2-dDCB and 2-tDCB (orally, up to 2000mg/kgbw/day), we did not detect any clastogenic effects. Furthermore, DNA strand-breaks were not detected in the in vitro comet assay with CHL/IU cells, and DNA adducts derived from 2-dDCB and 2-tDCB were not detected in the colon tissues of the mice used for the micronucleus tests, in rats from a repeated dose 90-day oral toxicity test (0.03% 2-tDCB in the diet), or in rats from the AOM-induced carcinogenesis study (0.025% 2-tDCB in the diet). An in vitro tumour-promotion assay with Bhas 42 cells revealed that the number of transformed foci increased significantly following treatment of cells in the stationary phase with 2-dDCB or 2-tDCB for 10 days.Our results indicate that neither 2-dDCB nor 2-tDCB were genotoxic chemicals. However, they exhibited promoting activity, at least in vitro, when Bhas 42 cells were continuously exposed to these chemicals at toxic doses.

The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies

Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci–adenoma–carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS–treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.

Abstract B34: Association of endogenous oxidative and aldehyde stress: Implications for studies of colon carcinogenesis

Abstract The results of a small pilot study provided new insights into the process of colon carcinogenesis. Background: The known risk factors for colorectal cancer (CRC) suggested that CRC resulted from the interaction of exposure to energy excess and to oxidative stress [McKeown-Eyssen G et al. pp 673-693 in “Endogenous Toxins” Wiley, 2010]. The suggestion was supported by: cellular studies that demonstrated the cytotoxicity and genotoxicity of excess energy substrate (fructose) with oxidative stress (H2O2); animal studies that showed a wide range of pathology associated with fructose-based diets when combined with oxidative stress; and clinical studies that described the association of advanced glycation end-products (AGEs) with chronic diseases associated with the Western lifestyle. Methods: A pilot case-control study at a hospital-based gastroenterology clinic was conducted to assess methods for future tests of the hypothesis. It was based on an analysis of plasma samples collected from patients with (n = 20) or without (n = 21) colonoscopy-demonstrated polyps. Results: Although as anticipated none of the differences between polyp and non-polyp plasma samples achieved statistical significance, there were unexpectedly strong associations of the concentrations of the endogenous plasma aldehydes, glyoxal and methylglyoxal (r = 0.92), and glyoxal and 4-hydroxynonenal (r = 0.52) across the collected samples. Conclusions: The associations were likely a consequence of the known interaction of endogenous aldehydes with oxidative stress: endogenous aldehydes increased oxidative stress; oxidative stress increased the formation of endogenous aldehydes [e.g. Vander Jagt DL. Drug Metab Drug Interact 2008;23:93-124]. The products of such interactions, AGEs and advanced lipid oxidation endproducts (ALEs), could explain the known accumulation of fluorescent lipofuscin observed with dysplastic adenomas. Impact: Exposure to endogenous aldehydes and oxidation products is complex. Endogenous aldehyde derived — AGEs could provide robust biomarkers of this exposure including information relating to the tissues, cells and cellular organelles affected. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B34.

Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

BackgroundAzoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats.MethodsFor gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 × 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 × 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent).ResultsMicroarray gene expression analysis showed that Defcr4, Igfbp5, Mmp7, Nos2, S100A8 and S100A9 were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), while Slc26a3, Mptx, Retlna and Muc2 were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFα/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 including Apc.ConclusionThe results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of genomic imbalance, it is interesting to note that one of the alterations concerned Apc, a key gene in colorectal carcinogenesis. The fact that many of the molecular alterations described in this study are documented in human colon tumours confirms the relevance of DMH-induced cancers as a powerful tool for the study of colon carcinogenesis and chemoprevention.

Reduced Rank Mixed Effects Models for Spatially Correlated Hierarchical Functional Data

Hierarchical functional data are widely seen in complex studies where subunits are nested within units, which in turn are nested within treatment groups. We propose a general framework of functional mixed effects model for such data: within-unit and within-subunit variations are modeled through two separate sets of principal components; the subunit level functions are allowed to be correlated. Penalized splines are used to model both the mean functions and the principal components functions, where roughness penalties are used to regularize the spline fit. An expectation–maximization (EM) algorithm is developed to fit the model, while the specific covariance structure of the model is utilized for computational efficiency to avoid storage and inversion of large matrices. Our dimension reduction with principal components provides an effective solution to the difficult tasks of modeling the covariance kernel of a random function and modeling the correlation between functions. The proposed methodology is illustrated using simulations and an empirical dataset from a colon carcinogenesis study. Supplemental materials are available online.

Bayesian variable selection in clustering high-dimensional data with substructure

In this article we focus on clustering techniques recently proposed for high-dimensional data that incorporate variable selection and extend them to the modeling of data with a known substructure, such as the structure imposed by an experimental design. Our method essentially approximates the within-group covariance by facilitating clustering without disrupting the groups defined by the experimenter. The method we adopt simultaneously determines which expression patterns are important, and which genes contribute to such patterns. We evaluate performance on simulated data and on microarray data from a colon carcinogenesis study. Selected genes are biologically consistent with current research and provide strong biological validation of the cluster configuration identified by the method.

Mouse models for the study of colon carcinogenesis

The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma-carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.

Coordinated p27 Kip1 expression as a function of distance between crypts ‐ Potential inter‐crypt signaling

Colonic epithelial cells are arranged in patterns called crypts. There has been a conjecture that a coordinated response exists at the crypt level, i.e. that biological responses in one crypt affects the biological responses in neighboring crypts. P27Kip1 (p27) is a cyclin dependent kinase inhibitor, which arrests cell cycle progression and induces apoptosis. We hypothesized if a crypt has high p27 expression, the neighboring crypts are likely to have high p27 expression. To test the hypothesis, 20 colonic crypts in each of 12 rats were analyzed for p27 levels and the distance between the crypts were measured. The correlation between the p27 expression between the crypts were analyzed using Bayesian statistical methods. The correlation at 25 μm was 0.57 and the correlation was positive for distances up to 400 μm (p<0.05). The closer crypts were to one another the better the correlation. This observation supports the existence of inter‐crypt signaling; p27 expression in crypts which are in close proximity tend to have similar expression levels. This type of inter‐crypt signaling may be responsible for the formation of aberrant crypt foci, polyps and eventually colon adenomas. This spatial analysis is a novel mathematical approach to study of colon carcinogenesis. Funded by NIH (CA61750, CA82907, CA59034), NSBRI NASA NCC 9–58 and NIEHS P30‐ES09106.

Semiparametric latent covariate mixed-effects models with application to a colon carcinogenesis study.

We study a mixed-effects model in which the response and the main covariate are linked by position. While the covariate corresponding to the observed response is not directly observable, there exists a latent covariate process that represents the underlying positional features of the covariate. When the positional features and the underlying distributions are parametric, the expectation-maximization (EM) is the most commonly used procedure. Though without the parametric assumptions, the practical feasibility of a semi-parametric EM algorithm and the corresponding inference procedures remain to be investigated. In this paper, we propose a semiparametric approach, and identify the conditions under which the semiparametric estimators share the same asymptotic properties as the unachievable estimators using the true values of the latent covariate; that is, the oracle property is achieved. We propose a Monte Carlo graphical evaluation tool to assess the adequacy of the sample size for achieving the oracle property. The semiparametric approach is later applied to data from a colon carcinogenesis study on the effects of cell DNA damage on the expression level of oncogene bcl-2. The graphical evaluation shows that, with moderate size of subunits, the numerical performance of the semiparametric estimator is very close to the asymptotic limit. It indicates that a complex EM-based implementation may at most achieve minimal improvement and is thus unnecessary.

Nonparametric estimation of correlation functions in longitudinal and spatial data, with application to colon carcinogenesis experiments

In longitudinal and spatial studies, observations often demonstrate strong correlations that are stationary in time or distance lags, and the times or locations of these data being sampled may not be homogeneous. We propose a nonparametric estimator of the correlation function in such data, using kernel methods. We develop a pointwise asymptotic normal distribution for the proposed estimator, when the number of subjects is fixed and the number of vectors or functions within each subject goes to infinity. Based on the asymptotic theory, we propose a weighted block bootstrapping method for making inferences about the correlation function, where the weights account for the inhomogeneity of the distribution of the times or locations. The method is applied to a data set from a colon carcinogenesis study, in which colonic crypts were sampled from a piece of colon segment from each of the 12 rats in the experiment and the expression level of p27, an important cell cycle protein, was then measured for each cell within the sampled crypts. A simulation study is also provided to illustrate the numerical performance of the proposed method.

Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents.

Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the beta-catenin gene in its GSK-3beta phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of beta-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of beta-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of beta-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (iNOS) and the inducible type of cyclooxygenase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of iNOS is an early and important event occurring in step with beta-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of iNOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E(2) (PGE(2)) receptors may be altered in colon cancers. For example, the EP(1) and EP(2) subtypes have been shown to be up-regulated and EP(3) down-regulated in AOM-induced colon cancers in rats and mice. EP(1) and EP(4) appear to be involved in ACF formation, while alteration in EP(2) and EP(3) is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/beta-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man.

Novel inhibition of matrix metalloproteinases, angiogenesis, and tumour cell invasion by captopril

and their combinations were hybridized m situ to the tumor chromosomes. Genetic alterations were a*ralysed using the Sky'View sofiware.We were able to isolate and cuhivate five carcinoma cell fines (Geki 1,3,4,5,7) and one adenoma cell line (Geki 2) and analyse the genetic abenations, Neither the adenoma cell line (G,eki-2) nor four of the carcinoma cell lines (Geki 1,3,5,7) revealed striking chromosomal changes, in contrast, Geki-4 showed both uumerical and structural aberrations The complete karyotype was: (75,XXX, + der(1)t(1;l 7), + der(2)t(2; 18), + 3,-4, + der(4)t(4; 6), + 5, + der7, + 8, + der(9) t(9;11) , 11, + der( 11 )t( 11 ;20), + 12 + 13 + 16,-18, + 20x2, + X). Comparison of early and later passages of one case (Geki-5) revealed an increase of structural chromosomal changes with increasing passages. Compared to commerciafiy available cell lines of colon carcinoma, our own established cell lines show significantly fewer chromosomal anomalies, although changes increase dunng cultivation The numerous alterations detected in commercial cell lines may partly be due to artefacts of cell culture and may intluence the expression of multiple genes and consequently geno|ype and phenotype of the cells. This emphasizes the importance of using early passages of cell lines for valid in vitro studies of carcinogenesis, The cefi lines established and characterized in the present study appear to be good candidates for further investigation. In pantcular, the adenoma cell line Geki-2 offers new possibilities for further in vitro studies of colon carcinogenesis

Dietary lectins can stimulate pancreatic growth in the rat.

Lectins are proteins or glycoproteins of nonimmune origin, which bind specifically to carbohydrate structures. They are widespread in the human diet, and many are resistant to digestion. High doses of lectins have been shown to stimulate intestinal and pancreatic growth. The aim of the present study was to investigate the long-term actions of low doses of lectins on the rat intestine and pancreas. A long-term carcinogenesis study was performed using low levels (40 micro g/rat/day) of peanut (PNA) or mushroom lectin (ABA) which bind to O-linked (mucin-type) oligosaccharides in the gut. While this was primarily designed as a colon carcinogenesis study, the pancreas was also investigated. No significant changes in colon carcinogenesis were seen, however, the colons were slightly heavier in the lectin treated groups. The weight of the pancreas was significantly greater (by 18 and 23%) in both lectin treated groups (P < 0.03/0.001). The weights of the acini and septal tissue were also increased by 39-46% in PNA and ABA fed animals, respectively (P < 0.002); there was no significant change in the endocrine pancreas. In conclusion, long-term feeding of low doses of lectin can influence pancreatic growth, and this trophic action may have potential adverse implications for the development of pancreatic cancer in humans.

Collaborative validation study of the in vivo micronucleus test using mouse colonic epithelial cells

The in vivo micronucleus test using mouse colonic epithelial cells was evaluated as the 11th collaborative study organized by the Collaborative Study Group on the micronucleus test (CSGMT) with three model chemicals that were known to induce chromosome damage in mouse colonic cells. Five laboratories participated in this validation study. All three model chemicals, i.e. 1,2-dimethylhydrazine dihydrochloride (1,2-DMH), N-methyl- N-nitrosourea (MNU), and mitomycin C (MMC), induced micronucleated colonic epithelial cells in a 4-day exposue protocol in all participating laboratories. We confirmed that the present single cell suspension method could be used to detect the model chemicals as micronucleus inducers in mouse colonic epithelial cells. Advantages of this method are that experiments are easy to perform and that intact cells can be analyzed. The present study suggested that the colon micronucleus assay proposed here is useful for mechanistic studies of colon carcinogenesis.

Effects of vitamins A and E on methylazoxymethanol-induced mutagenesis in Salmonella typhimurium strain TA100

The aim of this study is to report the antimutagenic effect of vitamin A and vitamin E towards methylazoxymethanol (MAM)-induced mutagenesis in Salmonella typhimurium strain TA100 sensitive to alkylating agents. In order to characterize different levels of action of these two fat-soluble vitamins towards the mutagenicity of MAM, several assays have been considered to show the antimutagenic effect and the possible interactions of vitamins with MAM or with the bacteria. Thus, for each vitamin, three different assays with three different incubations have been conducted: (i) MAM, bacteria and vitamins together, (ii) MAM and vitamins, (iii) bacteria and vitamins. The results showed that both vitamins A and E present an antimutagenic effect towards MAM induced mutagenesis. α-Tocopherol seems to have an action directly on to the mutagenic agent, whereas the action of retinol is likely due to a protection of the bacterial genoma against MAM. These in vitro results could help to interpret results of colon carcinogenesis studies using animals induced by 1,2-dimethylhydrazine and fed vitamins supplemented diet.

Influence of tea catechins on the digestive tract

Tea catechins undergo various metabolic changes after they are taken orally, though a large percentage are excreted intact with the feces. Epidemiological studies suggest a protective effect of tea against various human cancers, including colon and rectum. The bactericidal property of tea catechins plays several roles in the digestive tract. In the small intestine, catechins inhibit alpha-amylase activity, and a certain amount is absorbed into the portal vein. Although catechins are bactericidal, they do not affect lactic acid bacteria. Including tea catechins in the diet for several weeks decreases putrefactive products and increases organic acids by lowering pH. These changes were achieved in tube-fed patients by administering 100 mg of tea catechins (equivalent to a cup of green tea) three times daily with meals for 3 weeks. When catechin administration ceased, the effects reversed after 1 week. Catechins should be considered further in colon carcinogenesis studies.

Cell kinetic analysis of intact rat colonic crypts by confocal microscopy and immunofluorescence

BACKGROUND & AIMS: Precise quantitative and spatial analysis of cell cycle-related biomarkers in colonic crypts is often vital for studies of colon carcinogenesis and cancer prevention. To overcome the limitations of histology, confocal laser microscopy of microdissected whole crypts was used to quantitate S phase and mitotic cells. METHODS: Microdissected distal colonic crypts were studied in a modified rat starvation refeeding model. S phase cells were labeled in vivo with 5- bromodeoxyuridine. Mitotic cells were labeled with MPM2 (antibody to mitosis-specific epitope) and also assessed for chromatin morphology with propidium iodide. Sequential optical crypt sections, produced by confocal microscopy, were digitally imaged. S phase labeling indices per whole crypt were also compared with those derived by conventional immunohistochemistry. RESULTS: S phase and mitotic cells were clearly discriminated without background staining. The labeled S phase cell number and fraction per whole crypt were significantly decreased with starvation and increased with refeeding. Variability in the labeling index between whole crypts analyzed by confocal microscopy was significantly smaller than between histological crypt sections. Consequently, the intervention contributed to 92.2% of the total variability of the labeling index in whole crypts but only to 59% of the variability in histological sections. CONCLUSIONS: Major limitations of histology are overcome by crypt microdissection and confocal microscopic analysis. The total crypt cell population as well as labeled M phase and S phase cells can be imaged, localized, and quantitated with improved precision. (Gastroenterology 1996 Dec;111(6):1493-500)

Hepatic pathology of the colon carcinogen, azoxymethane, in Hanford-Moore miniature pigs

Azoxymethane (AOM) is commonly used in colon carcinogenesis studies in rodents. In an attempt to develop a large animal model of human colon cancer, AOM was given to Hanford-Moore miniature pigs. Six pigs were injected intraperitoneally with a single dose of AOM of either 5, 10, 20, 40 or 55 mg per kg body weight. Within 48 h, severe signs of toxicity and death occurred in animals receiving greater than 20 mg per kg AOM. After 30 days, all surviving animals were killed and necropsied. Acute hepatic necrosis with haemorrhage was the major toxic effect of AOM in all animals receiving doses exceeding 20 mg per kg. In a second, longer-term experiment, eight pigs were injected with either 20 mg per kg AOM weekly or 10 mg per kg AOM every other week or a combination of both treatments. Chronic toxic effects were limited to the liver. No colon tumours were observed. It is concluded that this particular species demonstrates marked hepatic sensitivity to the toxic effects of AOM.

Animal Studies of Colon Carcinogenesis and Altered Epithelial Cell Differentiation

Chronic inflammatory bowel disease (IBD) appears to predispose to subsequent colon cancer. Factors that influence the degree of this risk require definition since the reported incidence of malignant change varies widely. Differing environmental factors such as diet may be critical, and several approaches have been used to explore the role of specific variables in colon cancer pathogenesis; one has employed the use of animal models. Naturally occurring models of colon cancer exist including cotton-topped tamarins with colitis. Best studied, however, are animal models of colon cancer induced with specific chemical carcinogens. Cycasin and hydrazine derivatives, eg, 1,2-dimethylhydrazine, are most widely used. After parenteral administration of an active carcinogen, metabolic activation occurs, resulting in colonic adenocarcinomas. Sessile and polypoid neoplasms may be induced, particularly in the distal colon, similar to human colon cancer. Using this model, the effect of differing dietary and therapeutic variables has been explored. Studies with purified single dietary fibres, such as microcrystalline cellulose and hemicellulose, but not pectin, have demonstrated reduced numbers of colonic tumours; these in vivo observations correlate with in vitro effects of fibres on rat luminal and fecal mutagenic activities. Specific therapies used in IBD have also been evaluated - metronidazole, for example, a bacterial mutagen, enhances the development of chemically induced rodent colon cancer. In addition, a significant increase in colonic tumour development occurs after intestinal resection or bypass, two procedures used in the surgical management of IBD. In this setting, surgical sutures, particularly nonabsorbable materials including stainless steel, may play a critical role. Although the extent and duration of disease in patients with chronic IBD may be important in colon cancer pathogenesis, other variables, including diet and treatment, may be critical modulating factors.