[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of the two fractions, aqueous (AEP) and ethanolic extracts of propolis (EEP) of the Brazilian propolis on azoxymethane (AOM)-induced aberrant crypt foci (ACF). Male Wistar Hannover (GALAS) rats were administered two weekly subcutaneous injections of AOM (20 mg/kg bw) and fed with diets mixed with AEP (100, 500 and 1,000 ppm) or EEP (500 and 1,000 ppm) for 4 weeks, starting one week before the first dosing of AOM. The modifying effects of the test extracts on ACF formation were assessed by counting the incidence and multiplicity of ACF at week 4. Proliferation cell nuclear antigen (PCNA)-labeling nuclei and apoptotic index were also immunohistochemically determined. Dietary supplementation with AEP and EEP significantly reduced the multiplicity of ACF with the effect of EEP being more potent than AEP. In the ACF and their surrounding non-lesional crypts, significantly lowered cell proliferation was observed in the rats, administered with AOM, and the extracts, while neither fraction affected the apoptotic index. Our findings suggest that AEP and EEP possess a chemopreventive ability in the early phase of colon carcinogenesis through the modulation of cell proliferation.
[Show abstract][Hide abstract] ABSTRACT: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are known to modulate carcinogenesis. In this study, we investigated whether a lipophilic HMG-CoA reductase inhibitor pitavastatin suppresses inflammation-related mouse colon carcinogenesis. Male CD-1 (ICR) mice were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and promoted by 2% (w/v) dextran sodium sulfate (DSS) in drinking water for 7 days. The experimental diets containing pitavastatin at 2 dose levels (1 and 10 ppm) were fed to male CD-1 (ICR) mice for 17 weeks, staring 1 week after the cessation of DSS exposure. The effects of dietary pitavastatin on colonic tumor development were assessed at Weeks 5, 10 and 20. Feeding with pitavastatin at both doses significantly inhibited the multiplicity of colonic adenocarcinoma at Week 20. Furthermore, the treatment significantly lowered the positive rates of proliferating cell nuclear antigen and increased the apoptotic index in the colonic epithelial malignancies. The treatment also reduced nitrotyrosine-positivity in the colonic mucosa. Our findings thus show that pitavastatin is effective in inhibiting colitis-related colon carcinogenesis through modulation of mucosal inflammation, oxidative/nitrosative stress, and cell proliferation.
International Journal of Cancer 11/2007; 121(10):2331-9. DOI:10.1002/ijc.22976 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conjugated fatty acids (CFA) being novel type of biologically functional lipid substances, have received increased interest owing to their beneficial effects on human health. Among CFAs, conjugated linoleic acids (CLA) have been reviewed extensively for their occurrence, health benefits, industrial production and applications. On the contrary, it is worth noting that some plant seeds contain conjugated linolenic acids (CLN) at considerably higher levels (30 to 70 wt% lipid), although other kinds of CFAs including CLA are only found at concentrations less than 1% in natural products. It is thus imperative that CLN are the only CFAs that occur in higher quantities in nature and we have extensively screened CLN from different plant seed oils for their chemopreventive effects. In the ensuing review, we describe in detail the physiological functions of CLN isomers that occur in some plant seeds. CLN from natural origin showed growth inhibitory and apoptotic effects on cancer cells and the activity was dependent on their geometrical/positional structures. All trans CLN exerted stronger growth inhibition and more DNA fragmentation in human colon cancer cells than corresponding CLN isomer with cis configuration. CLN induced apoptosis through decrease of Bcl-2 protein. It will be interacted with increase in PPARγ signaling and up-regulation of gene expression of GADD45 and p53. Enhancement of PPARγ expression was also observed in the rats fed seed oil rich in CLN. Dietary feeding of these CLN-containing seed oil reduced the frequency of colonic aberrant crypt foci (ACF) in rat that is the precursor of colon carcinogenesis in short-term experiment and inhibited the development of colonic adenocarcinoma in long-term experiment.
Current Nutrition & Food Science 10/2007; 3(4):309-318. DOI:10.2174/1573401310703040309
[Show abstract][Hide abstract] ABSTRACT: A novel heterocyclic amine, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), which is formed from nonmutagenic 9H-pyrido[3,4-b]indole (norharman) and aniline, is mutagenic to bacteria and mammalian cells and potently carcinogenic in rats. APNH is detected in human urine samples, suggesting that humans are continuously exposed to APNH. In the present study, (32)P-postlabelin analysis revealed that the levels of APNH-DNA adduct 24 hr after the treatment with APNH (1, 5 and 20 mg/kg body weight) in male ICR mice were increased in a dose-dependent manner in the colon and liver. Based on these findings, we determined the tumor-initiating potency of APNH in an inflammation-related and two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were given a single intragastric administration (1, 2, 5 or 10 mg/kg body weight) of APNH and subsequent 1-week oral exposure to dextran sodium sulfate (DSS, 2% in drinking water). Treatment with APNH and DSS resulted in numerous colon tumor development: the incidence and multiplicity of the tumors were the highest in the mice received 10 mg/kg body weight of APNH and followed by DSS. Development of colon tumors was dose-dependent of APNH. Seven of 9 (77.8%) colonic adenocarcinomas developed in mice treated with APNH (10 mg/kg body weight) and DSS had beta-catenin gene mutations at codons 32 and 37, being predominantly transversion. These findings indicate that APNH has an initiating activity in inflamed mouse colon and the APNH-DNA adduct formation correlates with its tumorigenic potential.
International Journal of Cancer 10/2007; 121(8):1659-64. DOI:10.1002/ijc.22864 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the Apc(Min/+) mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the Apc(Min/+) mouse treated with DSS. Male C57BL/6J Apc(Min/+) and Apc(+/+) mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the Apc(Min/+) mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNFalpha and IL-1beta of colonic mucosa in the DSS-treated Apc(Min/+) mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc(+/+) mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the Apc(Min/+) mice.
International Journal of Cancer 08/2007; 121(3):506-13. DOI:10.1002/ijc.22736 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammation influences carcinogenesis. In the current study, we investigated whether ursodeoxycholic acid (UDCA) can inhibit colitis-related mouse colon carcinogenesis and compared it with the effects of sulfasalazine.
Male CD-1 mice were given a single i.p. injection of azoxymethane followed by 1-week oral exposure of 1% dextran sodium sulfate in drinking water. They are then maintained on a basal diet mixed with UDCA (0.016%, 0.08%, or 0.4%) or sulfasalazine (0.05%) for 17 weeks. At week 20, the tumor-inhibitory effects of both chemicals were assessed by counting the incidence and multiplicity of colonic neoplasms. The immunohistochemical expression of the proliferating cell nuclear antigen labeling index in colonic epithelial malignancies was also assessed. Finally, at week 5, the mRNA expressions for cyclooxygenase-2, inducible nitric oxide synthase, peroxisome proliferator-activated receptor-gamma, and tumor necrosis factor-alpha were measured in nontumorous mucosa.
Feeding the mice with UDCA at all doses significantly inhibited the multiplicity of colonic adenocarcinoma. The treatment also significantly lowered the proliferating cell nuclear antigen labeling index in the colonic malignancies. UDCA feeding reduced the expression of inducible nitric oxide synthase and tumor necrosis factor-alpha mRNA in the colonic mucosa, while not significantly affecting the expression of cyclooxygenase-2 mRNA and peroxisome proliferator-activated receptor-gamma mRNA. Sulfasalazine caused a nonsignificant reduction in the incidence and multiplicity of colonic neoplasia and did not affect these mRNA expression.
Our findings suggest that UDCA rather than sulfasalazine could serve as an effective suppressing agent in colitis-related colon cancer development in mice.
Clinical Cancer Research 05/2007; 13(8):2519-25. DOI:10.1158/1078-0432.CCR-06-2727 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent epidemiological studies have indicated that high dietary consumption of fruit and vegetables results in lower risk of bladder cancer. To confirm these findings, we investigated in the current study the effects of dietary administration with beta-cryptoxanthin extracted from Citras unshiu oranges on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis in mice. Male ICR mice were divided into 6 experimental and control groups. Groups 1 through 4 were given OH-BBN (500 ppm) in drinking water for 6 weeks to induced urinary bladder neoplasms. Mice in groups 2, 3 and 4 were fed the diets mixed with 1, 5 and 25 ppm of beta-cryptoxanthin, respectively, starting 1 week after the cessation of OH-BBN exposure, and kept on these diets for 24 weeks until the termination of the study. Group 5 was treated with the diet containing the test compound (25 ppm) alone, and group 6 served as an untreated control. All animals were sacrificed at week 32 for histopathology and immunohistochemistry (cyclin D1). Feeding with beta-cryptoxanthin decreased the incidence and multiplicity of preneoplastic and neoplastic lesions of urinary bladder. Notably, the highest dose (25 ppm) of the test chemical significantly lowered the occurrence of bladder carcinoma, in conjunction with reducing the cyclin D1-positive cell ratio. These findings suggest that beta-cryptoxanthin is able to prevent OH-BBN-induced bladder carcinogenesis in mice.
[Show abstract][Hide abstract] ABSTRACT: The current study was designed to investigate whether dietary citrus auraptene (AUR) suppresses the development of azoxymethane (AOM)-induced colorectal preneoplastic lesions in C57BL/KsJ-db/db (db/db) mice with obese and diabetic phenotypes. Female db/db and wild (+/+) mice were divided into the AOM + AUR, AOM alone, AUR alone, and the untreated groups in each phenotype. AOM was given 3 weekly intraperitoneal injections (10 mg/kg bw). AUR (250 ppm) was given in diet during the study (for 10 wk). Dietary AUR significantly reduced the number of aberrant crypt foci (ACF) and Beta -catenin-accumulated crypt (BCAC) in both phenotypes. The treatment also lowered cell proliferation activity and increased apoptotic cells in both lesions. Our findings indicate that dietary AUR is able to suppress the early phase of colon carcinogenesis in both phenotypes, suggesting possible application of AUR as a chemopreventive agent in both the high-risk and general populations for colorectal cancer.
Nutrition and Cancer 02/2007; 58(1):75-84. DOI:10.1080/01635580701308216 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of 9trans,11trans (9t,11t)-conjugated linoleic acid (CLA) isomer on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. Male F344 rats were given 2 weekly subcutaneous injections of AOM (20 mg/kg bw) to induce colonic ACF. They also were fed a diet containing either 0.01%, 0.1%, or 1% 9t,11t-CLA for 4 wk starting 1 wk before the first dosing of AOM. The group that received a diet supplemented with 9t,11t-CLA had a significantly lower number of ACF/colon in comparison to the AOM alone group in a dose-dependent manner up to 0.1%. Furthermore, treatment with 9t,11t-CLA induced apoptosis and suppressed cell proliferation activity in the non-lesional crypts. The downregulation of cyclooxygenase-2 and cyclin D1 and the activation of peroxisome proliferators activated receptor gamma were observed in the colonic mucosa of rats fed a diet supplemented with 9t,11t-CLA. Our findings thus provide some novel insight into the chemopreventive effect of 9t,11t-CLA against preinitiation as well as postinitiation stages of colorectal carcinogenesis.
Nutrition and Cancer 02/2007; 59(1):82-91. DOI:10.1080/01635580701419055 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people.
International Journal of Cancer 01/2007; 120(2):252-8. DOI:10.1002/ijc.22240 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study compared the growth inhibitory effects of pure conjugated linoleic acid (CLA) isomers [cis(c)9,c11-CLA, c9,trans(t)11-CLA, t9,t11-CLA, and t10,c12-CLA] on human colon cancer cell lines (Caco-2, HT-29 and DLD-1). When Caco-2 cells were incubated up to 72 h with 200 microM, each isomer, even in the presence of 10% fetal bovine serum (FBS), cell proliferation was inhibited by all CLA isomers in a time-dependent manner. The strongest inhibitory effect was shown by t9,t11-CLA, followed by t10,c12-CLA, c9,c11-CLA and c9,t11-CLA, respectively. The strongest effect of t9,t11-CLA was also observed in other colon cancer cell lines (HT-29 and DLD-1). The order of the inhibitory effect of CLA isomer was confirmed in the presence of 1% FBS. CLA isomers supplemented in the culture medium were readily incorporated into the cellular lipids of Caco-2 and changed their fatty acid composition. The CLA contents in cellular lipids were 26.2+/-2.7% for t9,t11-CLA, 35.9+/-0.3% for c9,t11-CLA and 46.3+/-0.8% for t10,c12-CLA, respectively. DNA fragmentation was clearly recognized in Caco-2 cells treated with t9,t11-CLA. This apoptotic effect of t9,t11-CLA was dose- and time-dependent. DNA fragmentation was also induced by 9c,11t-CLA and t10,c12-CLA. However, fragmentation levels with both isomers were much lower than that with t9,t11-CLA. t9t11-CLA treatment of Caco-2 cells decreased Bcl-2 levels in association with apoptosis, whereas Bax levels remained unchanged. These results suggest that decreased expression of Bcl-2 by t9t11-CLA might increase the sensitivity of cells to lipid peroxidation and to programmed cell death, apoptosis.
The Journal of Nutritional Biochemistry 01/2007; 17(12):830-6. DOI:10.1016/j.jnutbio.2006.01.007 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Catalpa (Catalpa ovata) seed oil (CPO) is a unique oil that contains a high amount of 9trans,11trans,13cis-conjugated linolenic acid. In the present study, we investigated whether dietary administration with CPO affects the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats to elucidate its possible cancer chemopreventive efficiency. Also, the effect of CPO on the fatty acid composition of liver tissue and colonic mucosa, the serum levels of total cholesterol and triglyceride, and the mRNA expression of cyclooxygenase (COX)-2 in the colonic mucosa were measured. In addition, the cell proliferation activity and apoptotic index in the colonic mucosa were estimated immunohistochemically. Animals were given two weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received the experimental diet containing 0.01%, 0.1% or 1% CPO for 4 weeks, starting one week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (99+/-28) at the end of the study (week 4). Dietary administration of CPO reduced the number of ACF (AOM + 0.01% CPO, 32+/-11, P<0.001; AOM + 0.1% CPO, 35+/-18, P<0.001; AOM + 1% CPO, 18+/-10, P<0.001). 9t,11t-conjugated linoleic acid was detected in the liver tissue and colonic mucosa of rats fed the CPO-containing diet. Additionally, dietary administration with CPO decreased the serum triglyceride level and the expression of COX-2 mRNA in the colonic mucosa. The indices of cell proliferation and apoptosis in the colonic mucosa of rats treated with AOM and 1% CPO have significant differences when compared with the AOM alone group. These findings suggest the possible chemopreventive activity of CPO in the early phase of colon carcinogenesis.
[Show abstract][Hide abstract] ABSTRACT: Effect of degraded lambda-carrageenan, which induces colitis in rodents, on the development of beta-catenin-accumulated crypts (BCAC) being putative precancer lesions of colon cancer was investigated in male DBA/2J mice initiated with azoxymethane (AOM). In a preliminary experiment, male DBA/2J mice among seven different strains (A/J, BALB/c, C3H/HeN, C57BL/6J, CBA/N, DBA/1J, and DBA/2J) of male mice were most sensitive to degraded lambda-carrageenan. Therefore, male DBA/2J mice were intraperitonially injected AOM (10 mg/kg body weight), and then 2% degraded lambda-carrageenan in drinking water for one or two weeks, starting one week after dosing of AOM. Thereafter animals were no further treated up to week 26. At week 26, the frequency of BCAC in the colonic mucosa was 12.50+/-2.46 in the AOM alone group, 11.30+/-3.50 in the AOM/degraded lambda-carrageenan (for one week) group, and 11.60+/-2.27 in the AOM/degraded lambda-carrageenan (for two weeks) group. The findings suggest that degraded lambda-carrageenan treatment for one or two weeks did not affect the occurrence of BCAC. Our results may indicate no enhancing or promoting effects of degraded lambda-carrageenan on colon carcinogenesis in mice initiated with AOM.
Cancer Letters 08/2006; 238(1):69-75. DOI:10.1016/j.canlet.2005.06.016 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although Apc(Min/+) mice are widely used for an animal model of human familial adenomatous polyposis (FAP), a majority of intestinal polyps locate in the small intestine. We recently reported that numerous beta-catenin-accumulated crypts (BCAC), which are reliable precursor lesions for colonic adenocarcinoma, develop in the large bowel of aged Apc(Min/+) mice. In this study, we determined the presence and location of BCAC in the large intestine of juvenile Apc(Min/+) mice (3 and 5 weeks of age). Surprisingly, BCAC were noted in the colon of even Apc(Min/+) mice of both ages, and mainly located in the distal and middle segments of the colon. Also, a few microadenomas were detected in Apc(Min/+) mice of 5-week old. Our results may indicate need of further investigation of the colorectal mucosa of Apc(Min/+) mice for examining colorectal carcinogenesis using Apc(Min/+) mice.
Cancer Letters 08/2006; 239(1):123-8. DOI:10.1016/j.canlet.2005.07.033 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously reported the chemopreventive ability of a prenyloxycoumarin auraptene in chemically induced carcinogenesis in digestive tract, liver and urinary bladder of rodents. The current study was designed to determine whether dietary feeding of auraptene and its related prenyloxycoumarin collinin can inhibit colitis-related mouse colon carcinogenesis. The experimental diets, containing the compounds at 2 dose levels (0.01 and 0.05%), were fed for 17 weeks to male CD-1 (ICR) mice that were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and promoted by 1% (w/v) DSS in drinking water for 7 days. Their tumor inhibitory effects were assessed at week 20 by counting the incidence and multiplicity of colonic neoplasms and the immunohistochemical expression of proliferating cell nuclear antigen (PCNA)-labeling index, apoptotic index, cyclooxygenase (COX)-2, inducible nitric oxide (iNOS) and nitrotyrosine in colonic epithelial malignancy. Feeding with auraptene or collinin, at both doses, significantly inhibited the occurrence of colonic adenocarcinoma. In addition, feeding with auraptene or collinin significantly lowered the positive rates of PCNA, COX-2, iNOS and nitrotyrosine in adenocarcinomas, while the treatment increased the apoptotic index in colonic malignancies. Our findings may suggest that certain prenyloxycoumarins, such as auraptene and collinin, could serve as an effective agent against colitis-related colon cancer development in rodents.
International Journal of Cancer 06/2006; 118(12):2936-42. DOI:10.1002/ijc.21719 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The modifying effects of dietary feeding with chrysin (5,7-dihydroxyflavone) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effect of chrysin on mitosis and apoptosis in 'normal appearing' crypts. To induce ACF, rats were given two weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received an experimental diet containing chrysin (0.001 or 0.01%) for 4 weeks, starting 1 week before the first dose of AOM. AOM exposure produced a substantial number of ACF (73+/-13/rat) at the end of the study (week 4). Dietary administration of chrysin caused significant reduction in the frequency of ACF: 0.001% chrysin, 37+/-17/rat (49% reduction, P<0.001); and 0.01% chrysin, 40+/-10/rat (45% reduction, P<0.001). In addition, chrysin administration significantly reduced the mitotic index and significantly increased the apoptotic index in 'normal appearing' crypts. These findings might suggest a possible chemopreventive activity of chrysin in the early step of colon tumorigenesis through modulation of cryptal cell proliferation activity and apoptosis.
[Show abstract][Hide abstract] ABSTRACT: Oral squamous cell carcinoma is one of the most common human neoplasms, and prevention of this malignancy requires a better understanding of its carcinogenesis process. To this end, we tried to establish an animal model using the human c-Ha-ras proto-oncogene-carrying transgenic (Tg) rats and the carcinogen 4-nitroquinoline 1-oxide (4-NQO). 4-NQO (20 p.p.m.) was administered to Tg and non-Tg rats for 8 weeks in their drinking water, and then the occurrence of tongue carcinogenesis was compared during the experimental period of 22 weeks. In addition, we determined the DNA ploidy in tongue lesions and examined the immunohistochemical expression of five biomarkers such as cyclin D1, glutathione S-transferase placental form, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and beta-catenin. Next, the cancer chemopreventive effects of nimesulide, pioglitazone and a synthetic geranylated derivative, which have been reported to be inhibitors of tongue carcinogenesis, were examined in Tg rats treated with 4-NQO. Either during or after treatment with 4-NQO in the drinking water, tongue dysplasia and tumors were observed on the tongues of both Tg and non-Tg rats, with a greater incidence and multiplicity in Tg rats. Histopathologically, squamous cell dysplasia, papilloma and carcinoma with or without invasion were present in the tongue. Immunohistochemistry revealed that expression levels against five biomarkers increase with disease progression, and the changes correlated with those of the DNA ploidy pattern. Interestingly, a strong expression of COX-2, iNOS and beta-catenin was observed on the invasive front of squamous cell carcinomas. A subsequent chemoprevention study using Tg rats showed that the chemicals tested suppressed the occurrence of tongue carcinomas when they were administered after 4-NQO-exposure. These results may thus indicate that our 4-NQO-induced Tg rat tongue carcinogenesis model simulates many aspects of human oral carcinogenesis and it can be applied for an analysis of oral cancer development while also helping to identify potentially effective cancer chemopreventive agents against oral cancer.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice.
Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1(-/-)), Mlh1 heterozygous (Mlh1(+/-)) and wild-type (Mlh1(+/+)) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, beta-catenin and p53.
Male and female Mlh1(-/-) mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1(+/-) and Mlh1(+/+) mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of beta-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis.
Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.
[Show abstract][Hide abstract] ABSTRACT: We have recently developed a mouse model for colitis-related colon carcinogenesis by a combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male ICR mice. However, strain differences in the sensitivity to AOM/DSS-induced colon carcinogenesis in mice have yet to be elucidated. The aim of this study was to determine the presence of any genetically determined differences in sensitivity to our model of colon carcinogenesis in four inbred strains of mice. Male Balb/c, C3H/HeN, C57BL/6N and DBA/2N mice were given a single intraperitoneal injection of AOM (10 mg/kg body wt), followed by 1% DSS (w/v) in drinking water for 4 days, and thereafter they received no further treatment for up to 16 weeks. At the end of the study (Week 18), all mice were killed and a histopathological analysis of their colon was performed. The incidence of colonic adenocarcinoma was 100% with a multiplicity (no. of tumors/mouse) of 7.7+/-4.3 in the Balb/c mice and 50% with a multiplicity of 1.0+/-1.2 in the C57BL/6N mice. On the other hand, only a few colonic adenomas, but no adenocarcinomas, developed in the C3H/HeN mice (29% incidence with a multiplicity of 0.7+/-1.5) and the DBA/2N mice (20% incidence with a multiplicity of 0.2+/-0.4). The inflammation and immunohistochemical nitrotyrosine-positivity scores of the mice treated with AOM and DSS in the decreasing order were as follows: C3H/HeN>Balb/c>DBA/2N>C57BL/6N and Balb/c>C57BL/6N>C3H/HeN>DBA/2N, respectively. Our results thus indicated the presence of strain differences in the susceptibility to AOM/DSS-induced colonic tumorigenesis. These differences may have been directly influenced by the response to nitrosation stress due to the inflammation caused by DSS.