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Aberrant Crypt Foci (aberrant + crypt_focus)
Selected AbstractsDNA methylation patterns in adenomas from FAP, multiple adenoma and sporadic colorectal carcinoma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Coral V.A. Wynter Abstract Colorectal adenomas have traditionally been regarded as homogeneous. The aim of our study was to identify molecular features that may differentiate sporadic adenomas from familial adenomas such as Familial Adenomatous Polyposis (FAP) and Multiple Adenoma patients. DNA methylation was tested at Methylated IN Tumor (MINT) loci (1,2,12,31) and the CpG promoter region of genes MLH1, HPP1, MGMT, p14ARF and p16INK4a in FAP-associated adenomas (33) from 5 patients with a known APC mutation (Group 1, FAP), adenomas (29) from 4 Multiple Adenoma patients (Group 2 Multiple), adenomas (14) from 3 patients with sporadic colorectal cancers showing high microsatellite instability (Group 3, MSI-H) and adenomas (16) from 7 patients, with sporadic colorectal cancers showing microsatellite stable or low level instability (Group 4, MSS/MSI-L). Aberrant Crypt Foci (ACFs), Hyperplastic Polyps (HPs) and cancers were also examined for methylation status as well as K- ras mutation. Multiple Adenoma patients were examined for germline polymorphisms in the base excision repair gene, MYH. The familial syndrome, FAP -associated adenomas showed a significantly low frequency of MINT methylation (15.5%,) compared to sporadic MSS/MSI-L-associated adenomas (35.5%). Group 3 (MSI-H) adenomas were different in that many showed serration and a high level of methylation (57.1%). Group 2, Multiple Adenoma cases, resembled sporadic MSS/MSI-L-associated adenomas. However the promoter regions of key genes, MGMT, p14ARF and p16INK4a were methylated to a greater extent than MINTs in both sporadic and familial adenomas. Genetic profiling of adenomas supports the concept that adenomas belonging to familial syndromes pursue a different pathway to tumorigenesis than their sporadic counterpar/ts from their earliest formation. © 2005 Wiley-Liss, Inc. [source] Testing for Spatial Correlation in Nonstationary Binary Data, with Application to Aberrant Crypt Foci in Colon CarcinogenesisBIOMETRICS, Issue 4 2003Tatiyana V. Apanasovich Summary. In an experiment to understand colon carcinogenesis, all animals were exposed to a carcinogen, with half the animals also being exposed to radiation. Spatially, we measured the existence of what are referred to as aberrant crypt foci (ACF), namely, morphologically changed colonic crypts that are known to be precursors of colon cancer development. The biological question of interest is whether the locations of these ACFs are spatially correlated: if so, this indicates that damage to the colon due to carcinogens and radiation is localized. Statistically, the data take the form of binary outcomes (corresponding to the existence of an ACF) on a regular grid. We develop score-type methods based upon the Matern and conditionally autoregressive (CAR) correlation models to test for the spatial correlation in such data, while allowing for nonstationarity. Because of a technical peculiarity of the score-type test, we also develop robust versions of the method. The methods are compared to a generalization of Moran's test for continuous outcomes, and are shown via simulation to have the potential for increased power. When applied to our data, the methods indicate the existence of spatial correlation, and hence indicate localization of damage. [source] Increased expression of fatty acid synthase in human aberrant crypt foci: Possible target for colorectal cancer preventionINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Kathleen E. Kearney Abstract Aberrant crypt foci (ACF), the earliest identified monoclonal lesions in the colon, provide insights into changes that promote and/or accompany the transformation of normal colonic epithelial cells to colorectal cancer. Fatty acid synthase (FAS), the primary enzyme involved in de novo lipogenesis from carbohydrates, is expressed at low levels in most normal human tissues but is elevated in several human neoplasms including colorectal adenomas and carcinomas. To determine if this pathway is altered even earlier in colorectal tumorigenesis, 35 human ACF from 21 patients were evaluated for the immunohistochemical expression of FAS. Sections of colon cancer served as positive controls, and normal colonic mucosa distant from cancer or ACF served as negative controls. FAS expression was increased in 30 (86%) ACF compared with that in adjacent normal colonic mucosa. The expression of FAS in ACF was not related to the degree of dysplasia or to the number of crypts in the ACF. The over expression of FAS in a high proportion of ACF suggests that this enzyme plays an important role very early in colorectal tumorigenesis and may be a target for chemoprevention. © 2009 UICC [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. [source] Hexosaminidase-altered Aberrant Crypts, Carrying Decreased Hexosaminidase , and , Subunit mRNAs, in Colon of 1,2-Dimethylhydrazine-treated RatsCANCER SCIENCE, Issue 2 2001Tetsuya Tsukamoto Aberrant crypt foci (ACF), consisting of morphologically irregular crypts, are thought to be precancerous lesions for colon cancers. For their molecular analysis, it is necessary to avoid contamination with adjacent normal crypts and stromal cells. Decreased hexosaminidase activity in ACF, which has been histochemically demonstrated, was used in the present study to classify isolated crypts in combination with morphological changes. The length, rim diameter, and width (average±SD, ,m) of hexosaminidase-positive (Hex+) crypts were 238.6±40.4, 89.5±22.9, and 57.6±14.0, respectively. For hexosaminidase-negative (Hex-) crypts, the values were 314.4±77.8, 140.3±45.7, and 97.3±34.7, the width being 1.69 tunes greater (P<0.0001). Crypts wider than 115 ,m (approximately 2 tunes the average size of Hex+ crypts) were all from ACF, judging from hexosaminidase staining. To analyze transcription levels of Hex , and , subunits (Hexa and Hexb, respectively), real-tune relative quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed using the LightCycler system. In aberrant crypts, both Hexa and Hexb were significantly down-regulated to 0.266 (P<0.002) and 0.131 (P<0.001) units, respectively, compared with those in morphologically normal crypts, with , -actin as the internal standard. This decrease could be a molecular marker for precancerous enzyme-altered ACF. [source] Modifying effect of propolis on dimethylhydrazine-induced DNA damage but not colonic aberrant crypt foci in ratsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2005Rodrigo O. Alves de Lima Abstract Propolis is a honeybee product with several biological and therapeutic properties, including antimutagenic and anticarcinogenic activities. The effects of an aqueous extract of propolis (AEP) were evaluated on the formation of 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) and DNA damage in the colon of male Wistar rats by the ACF and Comet assays, respectively. AEP was administered orally at 0.01%, 0.03%, 0.1%, and 0.3% in the drinking water, which resulted in doses of approximately 12, 34, 108, and 336 mg/kg body weight/day. Animals were also given a single subcutaneous injection of 40 mg/kg DMH and sacrificed 4 hr later for evaluating DNA damage, or 4 doses of 40 mg/kg DMH, administered 2 doses/week for 2 weeks, and sacrificed 12 weeks after the last injection for evaluating ACF development in the distal colon. Administration of AEP either simultaneously with or after the DMH treatment resulted in no statistically significant reduction of ACF. In contrast, 0.01%, 0.03%, and 0.3% AEP, given simultaneously with DMH, reduced DNA damage induction in the mid and distal colon. However, 0.3% AEP alone increased DNA damage in the colon. In conclusion, AEP had no effect on the formation of DMH-induced ACF in rat colon, but it modulated DMH-induced DNA damage in colon cells. Further investigations are recommended in order to establish the conditions under which propolis produces either protective or deleterious effects. Environ. Mol. Mutagen., 2005. © 2004 Wiley-Liss, Inc. [source] Increased expression of fatty acid synthase in human aberrant crypt foci: Possible target for colorectal cancer preventionINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Kathleen E. Kearney Abstract Aberrant crypt foci (ACF), the earliest identified monoclonal lesions in the colon, provide insights into changes that promote and/or accompany the transformation of normal colonic epithelial cells to colorectal cancer. Fatty acid synthase (FAS), the primary enzyme involved in de novo lipogenesis from carbohydrates, is expressed at low levels in most normal human tissues but is elevated in several human neoplasms including colorectal adenomas and carcinomas. To determine if this pathway is altered even earlier in colorectal tumorigenesis, 35 human ACF from 21 patients were evaluated for the immunohistochemical expression of FAS. Sections of colon cancer served as positive controls, and normal colonic mucosa distant from cancer or ACF served as negative controls. FAS expression was increased in 30 (86%) ACF compared with that in adjacent normal colonic mucosa. The expression of FAS in ACF was not related to the degree of dysplasia or to the number of crypts in the ACF. The over expression of FAS in a high proportion of ACF suggests that this enzyme plays an important role very early in colorectal tumorigenesis and may be a target for chemoprevention. © 2009 UICC [source] K-ras mutations and mucin profile in preneoplastic lesions and colon tumors induced in rats by 1,2-dimethylhydrazineINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Angelo Pietro Femia Abstract K-ras and mucin profile variations, associated with intestinal carcinogenesis, were studied in the preneoplastic lesions, mucin-depleted foci (MDF) and aberrant crypt foci (ACF), and in colonic tumors induced in rats by 1,2-dimethylhydrazine (DMH). The frequency of lesions with K-ras mutations was 23% (3/13), 5.5% (1/18) and 100% (14/14) in MDF, tumors and ACF, respectively. Two of three MDF mutated in K-ras also carried a missense mutation in Apc. We also tested the expression of MUC2, a mucin abundantly expressed in normal colon and M1/MUCA5C, up-regulated in colon carcinogenesis, using immunohistochemistry. MDF and tumors showed a dramatic reduction in the expression of MUC2, whereas ACF showed only a slight reduction. The expression of M1/MUC5AC was almost absent in normal mucosa, but was increased in all the lesions (MDF, tumors and ACF). The expression of the intestinal trefoil factor (ITF), a marker of goblet cell lineage, was reduced in MDF and tumors compared to normal mucosa but not in ACF. In conclusion, although K-ras mutations are present in all ACF, they are less frequent in MDF and tumors; M1/MUC5AC is a marker associated with all preneoplastic events while the reduction of MUC2 and ITF expression is selectively associated with more advanced lesions such as MDF and tumors. © 2007 Wiley-Liss, Inc. [source] Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane-induced rat colon carcinogenesis through elevation of colonic PPAR, expression and alteration of lipid compositionINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Hiroyuki Kohno Abstract Our previous short-term experiment demonstrated that seed oil from bitter melon (Momordica charantia) (BMO), which is rich in cis(c)9, trans(t)11, t13 -conjugated linolenic acid (CLN), inhibited the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). In our study, the possible inhibitory effect of dietary administration of BMO on the development of colonic neoplasms was investigated using an animal colon carcinogenesis model initiated with a colon carcinogen AOM. Male F344 rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks to induce colon neoplasms. They also received diets containing 0.01%, 0.1% or 1% BMO for 32 weeks, starting 1 week before the first dosing of AOM. At the termination of the study (32 weeks), AOM induced 83% incidence (15/18 rats) of colonic adenocarcinoma. Dietary supplementation with 0.01% and 0.1% BMO caused significant reduction in the incidence (47% inhibition by 0.01% BMO, p<0.02; 40% inhibition by 0.1% BMO, p<0.05; and 17% inhibition by 1% BMO) and the multiplicity (64% inhibition by 0.01% BMO, p<0.005; 58% inhibition by 0.1% BMO, p<0.02; and 48% inhibition by 1% BMO, p<0.05) of colonic adenocarcinoma, though a clear dose response was not observed. Such inhibition was associated with the increased content of CLA (c9,t11-18:2) in the lipid composition in colonic mucosa and liver. Also, BMO administration in diet enhanced expression of peroxisome proliferator-activated receptor (PPAR) , protein in the nonlesional colonic mucosa. These findings suggest that BMO rich in CLN can suppress AOM-induced colon carcinogenesis and the inhibition might be caused, in part, by modification of lipid composition in the colon and liver and/or increased expression of PPAR, protein level in the colon mucosa. © 2004 Wiley-Liss, Inc. [source] Dietary-feeding of grape seed extract prevents azoxymethane-induced colonic aberrant crypt foci formation in fischer 344 ratsMOLECULAR CARCINOGENESIS, Issue 7 2010Balaiya Velmurugan Abstract Chemoprevention by dietary agents/supplements has emerged as a novel approach to control various malignancies, including colorectal cancer (CRC). This study assessed dietary grape seed extract (GSE) effectiveness in preventing azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation and associated mechanisms in Fischer 344 rats. Six-week-old rats were injected with AOM, and fed control diet or the one supplemented with 0.25% or 0.5% (w/w) GSE in pre- and post-AOM or only post-AOM experimental protocols. At 16,wk of age, rats were sacrificed and colons were evaluated for ACF formation followed by cell proliferation, apoptosis, and molecular analyses by immunohistochemistry. GSE-feeding caused strong chemopreventive efficacy against AOM-induced ACF formation in terms of up to 60% (P,<,0.001) reduction in number of ACF and 66% (P,<,0.001) reduction in crypt multiplicity. Mechanistic studies showed that GSE-feeding inhibited AOM-induced cell proliferation but enhanced apoptosis in colon including ACF, together with a strong decrease in cyclin D1, COX-2, iNOS, and survivin levels. Additional studies showed that GSE-feeding also decreased AOM-caused increase in ,-catenin and NF-,B levels in colon tissues. Compared to control animals, GSE alone treatment did not show any considerable change in these biological and molecular events in colon, and was nontoxic. Together, these findings show the chemopreventive efficacy of GSE against the early steps of colon carcinogenesis in rats via likely targeting of ,-catenin and NF-,B signaling, and suggest its potential usefulness for the prevention of human CRC. © 2010 Wiley-Liss, Inc. [source] Differential apoptosis by gallotannin in human colon cancer cells with distinct p53 statusMOLECULAR CARCINOGENESIS, Issue 3 2007Sahar Al-Ayyoubi Abstract Gallotannin (GT), a plant polyphenol, has shown anticarcinogenic activities in several animal models including colon cancer. In our previous study, we showed that GT inhibits 1,2-dimethylhydrazine-induced colonic aberrant crypt foci and tumors in Balb/c mice, thus supporting a role for GT as a chemopreventive agent in colon cancer. However, at the molecular level, GT's mechanism of chemoprevention is still unclear. In this study, we aim at identifying GT's potential molecular mechanisms of action in in vitro studies. We show that GT differentially inhibits the growth of two isogenic HCT-116 (p53+/+, p53,/,) human colon cancer cells versus normal human intestinal epithelial cells (FHs 74Int). DNA flow cytometric analysis showed that GT induced S-phase arrest in both HCT-116 cell lines. Cell-cycle arrest in p53 (+/+) cells was associated with an increase in p53 protein levels and p21 transcript and protein levels. The inhibition of cell-cycle progression of HCT-116 p53 (+/+) cells by GT correlated with a reduction in the protein levels of cyclin D1, pRb, and the Bax/Bcl-2 ratio. Although GT did not induce apoptosis in p53 (+/+) cells, a significant induction of apoptosis was observed in p53 (,/,) cells as shown by TUNEL staining and flow cytometry analysis. Apoptosis induction in p53 (,/,) cells was associated with a significant increase in Bax/Bcl-2 protein levels. Our results demonstrate that GT inhibits the growth of HCT-116 colon cancer cells in a p53-independent manner but exhibits differential sensitivity to apoptosis induction in HCT-116 cells with distinct p53 status. © 2006 Wiley-Liss, Inc. [source] DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2-Amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) or 2-Amino-3-methylimidazo[4,5- f]quinoline (IQBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2000Inger-Lise Steffensen Epidemiological studies indicate that rapid acetylators with a high intake of well-done red meat have an increased risk of colorectal cancer. Arylamine N -acetyltransferase enzymes (E.C. 2.3.1.5) activate carcinogenic heterocyclic amines found in the crust of fried meat via O -acetylation of their N -hydroxylamines to reactive intermediates that bind covalently to DNA and produce mutations. Syrian hamsters as well as humans express two N -acetyltransferase isozymes (NAT1 and NAT2) which differ in substrate specificity and genetic control. Nucleic acid substitutions in the NAT2 gene segregate individuals into rapid, intermediate and slow acetylator phenotypes. In the present paper, we examined the role of the polymorphic NAT2 acetylator genotype in carcinogenesis induced by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5- f]quinoline (IQ) by comparing Syrian hamster lines congenic at the NAT2 locus. No differences were found between rapid and slow acetylator congenic hamsters in levels of intestinal PhIP-DNA adducts. In contrast to previous studies in rats, no carcinogen-related induction of the preneoplastic lesions aberrant crypt foci or tumors was found in the intestines of rapid and slow acetylator congenic Syrian hamsters administered PhIP or IQ. [source] Chemoprevention of lung cancer by lycopeneBIOFACTORS, Issue 1-4 2000Dae Joong Kim Abstract An investigation was conducted to assess the chemopreventive potential of lycopene (LP), a naturally occurring hydrocarbon carotenoid found in tomatoes and their products, administered during the post-initiation stage in a multiorgan carcinogenesis model. One hundred eighteen B6C3F_1 mice of both sexes were subjected to combined treatment with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU) and 1,2-dimethylhydrazine (DMH) from day 11 after birth to week 9 (DMD treatment) (groups 1 and 2) or given their vehicles (group 3). Then group 1 received LP (25 or 50 ppm in drinking water) for 21 weeks from weeks 11 to 32. Group 2 served as a carcinogen alone control and group 3 was given only LP (25 or 50 ppm). The incidences and multiplicities of lung adenomas plus carcinomas combined in male mice in group 1 receiving LP 50 ppm were significantly decreased as compared to the DMD alone or DMD and LP 25 ppm group values (75.0 vs 18.8%, P < 0.02; 0.94 ± 0.17 vs 0.25 ± 0.14, P < 0.001). While hepatocellular carcinomas were lacking in the DMD and LP groups, two cases were found in the DMD alone group (not statistically significant). The values for aberrant crypt foci (ACF) and tumors in the colon and kidney did not show any significant variation among the carcinogen-treated subgroups. The results of this study provide evidence that the tomato carotenoid, lycopene, may have potential as a chemopreventive agent against carcinogenesis in the male lung. [source] Chemopreventive effects of coffee bean and rice constituents on colorectal carcinogenesisBIOFACTORS, Issue 1-4 2000Hideki Mori Abstract Polyphenolic compound chlorogenic acid (CGA) known to be much contained in coffee beans was found to have a regressive effect on induced aberrant crypt foci (ACF) as well as on development of ACF in azoxymethane (AOM)-induced colorectal carcinogenesis in rats. Rice germ and ,-aminobutyric acid-enriched defatted rice germ inhibited AOM-induced ACF formation and colorectal carcinogenesis in rats. Ferulic acid (FA) also known to be contained in coffee beans and rice prevented AOM-induced ACF formation and intestinal carcinogenesis in rats. Both of food factors, coffee and rice may be of benefit to prevention of human colorectal cancers. [source] Testing for Spatial Correlation in Nonstationary Binary Data, with Application to Aberrant Crypt Foci in Colon CarcinogenesisBIOMETRICS, Issue 4 2003Tatiyana V. Apanasovich Summary. In an experiment to understand colon carcinogenesis, all animals were exposed to a carcinogen, with half the animals also being exposed to radiation. Spatially, we measured the existence of what are referred to as aberrant crypt foci (ACF), namely, morphologically changed colonic crypts that are known to be precursors of colon cancer development. The biological question of interest is whether the locations of these ACFs are spatially correlated: if so, this indicates that damage to the colon due to carcinogens and radiation is localized. Statistically, the data take the form of binary outcomes (corresponding to the existence of an ACF) on a regular grid. We develop score-type methods based upon the Matern and conditionally autoregressive (CAR) correlation models to test for the spatial correlation in such data, while allowing for nonstationarity. Because of a technical peculiarity of the score-type test, we also develop robust versions of the method. The methods are compared to a generalization of Moran's test for continuous outcomes, and are shown via simulation to have the potential for increased power. When applied to our data, the methods indicate the existence of spatial correlation, and hence indicate localization of damage. [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] Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodentsCANCER SCIENCE, Issue 6 2004Mami Takahashi 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 ,-catenin gene in its GSK-3, phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of p-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of ,-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of ,-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 cyclooxyge-nase (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 ,-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 E2 (PGE2) receptors may be altered in colon cancers. For example, the EP, and EP2 subtypes have been shown to be up-regulated and EP3 down-regulated in AOM-induced colon cancers in rats and mice. EP, and EP4 appear to be involved in ACF formation, while alteration in EP2 and EP3 is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/,-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. [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. [source] Early cellular events in colorectal carcinogenesisCOLORECTAL DISEASE, Issue 2 2002A. G. Renehan Colorectal cancer develops through a multistage process recognizable at a histopathological level by progression from normal mucosa to invasive carcinoma (the adenoma-carcinoma sequence). For many years, it has been hypothesized that increased cell proliferation in the colonic crypt represents the earliest recognizable stage in this sequence. This perspective is now changing. While several human studies have reported increased crypt cell proliferation in samples from at-risk patients, there are many inconsistencies and paradoxes in their conclusions. In addition, it is appreciated that the process of apoptosis (programmed cell death) is vital for normal crypt homeostasis and its impairment may be an early event in the neoplastic process. It is now believed that aberrant crypt foci (ACFs) represent the earliest step in colorectal carcinogenesis. Two ACF types are identifiable: hypercellular and dysplastic. Increased proliferative activity may be seen in both, but the dysplastic entity is most relevant to carcinogenesis. Animal and human studies support the notion that ACFs grow by crypt fission leading to the formation of microadenomas. Adenomas are monoclonal expansions of an altered cell, but very early lesions may be polyclonal. There are outward and inward theories of polypoid growth, and evidence to support both mechanisms. The ACF assay has become a useful tool to detect carcinogens in animal studies but has been less frequently used in human studies. For future cancer chemopreventive and risk assessment studies in humans, the identification and quantification of ACFs should be considered a more effective intermediate marker of risk than the determination of crypt cell proliferation alone. [source] | |||||||||||||