Suppressing effect of perilla oil on azoxymethane-induced foci of colonic aberrant crypts in rats

We have investigated the modulatory effect of dietary perillaoil which is rich in the n-3 polyunsaturated fatty acid,     

Evidence for ras gene mutation in 2-amino-3-methylimidazo[4,5-f]quinoline–induced colonic aberrant crypts in the rat

Aberrant crypt foci (ACF) are putative peneoplastic lesions that develop after treatment of animals with colon carcinogens, including cooked-meat heterocyclic amines such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 rats given IQ by gavage on alternating days for 2 wk (130 mg/kg body weight) and killed 12 wk after the final carcinogen dose had an average of 4.4 ACF/colon and an average of 3.2 crypts/focus. The DNA from these ACF was amplified by the polymerase chain reaction and analyzed by 3′-primer mismatch and direct sequencing methods for mutations in the Ki-ras proto-oncogene. Of the 37 IQ-induced ACF screened, three contained a GGT→GAT mutation in codon 12 and one contained a GGC→GCC mutation in codon 13. The approximately 11% frequency of mutation in IQ-induced ACF is within the range of previous ACF studies of azoxymethane, which reported a 7–37% incidence of Ki-ras mutaion. These findings suggest that for both compounds, ras mutations occur during early stages of colorectal tumorigenesis. However, while ras mutations can be detected with increasing frequency in azoxymethane-induced adenomas and carcinomas, they are reportedly absent in IQ-induced colon tumors. Thus, for IQ and related compounds additional factors (possibly increased cell proliferation) may be important in the later stages of colorectal tumorigenesis. © 1995 Wiley-Liss Inc.     

Prevention by chemopreventive agents of azoxymethane-induced foci of aberrant crypts in rat colon.

Foci of aberrant crypts are putative preneoplastic lesions of colon cancer that can be detected in unsectioned colons stained with methylene blue. The ability of this assay to demonstrate chemopreventive activity was evaluated. Male Sprague-Dawley rats received two subcutaneous injections 1 week apart, of 15 mg/kg azoxymethane each. The animals started to receive the test agents in their diet 1 week prior to the first injection of azoxymethane and continuously until killed 5 weeks later. The number of foci of aberrant crypts induced by the treatment of azoxymethane was reduced from 228 foci/animal without any chemopreventive agent to 151 foci/animal by N-acetylcysteine; to 121 foci/animal by dehydroepiandrosterone; to 161 by alpha-difluoromethylornithine; and to 121 by 1,2-oxothiazolidine-4-carboxylate. The other agents (diallyl sulfide, ellagic acid and phenethyl isothiocyanate) did not significantly alter the number of foci/animal induced by azoxymethane. Animals that did not receive azoxymethane had an average of 0.72 foci/animal. Our results suggest that four of the tested agents might reduce azoxymethane-induced colon cancer, which requires confirmation. Further validation of the foci of aberrant crypt in the colon assay to screen chemicals for chemoprevention agents is warranted.     

Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents

Foci of aberrant and/or hexosaminidase-negative crypts in ratcolon are putative precancerous lesions that have been proposedas biomarkers for Short-term bioassays for chemical carcinogensand chemopreventive agents. The ability of a substance to reducethe yield of azoxymethane (AOM)- induced foci in the colon ofmale Fischer 344 rats, was evaluated as a screening assay forchemopreventive agents. Twenty-eight test agents were administeredcontinuously in the diet from the start of the experiments untilthe animals were killed 35 days later. AOM was s.c. administeredeither as 15 mg/kg body wt on days 7 and 14 or as 30 mg/kg bodywt on day 7 of the experiment. Foci of aberrant crypts wereevaluated in whole mounts of methylene blue-stained colons.AOM induced twice as many foci when administered between 8.40and 11.00 a.m. than between 2.45 and 5.55 p.m. Calcium saltsof carbonate, chloride and glucarate decreased the yield ofAOM-induced foci while the acidic salts of lactate and phosphatedid not inhibit the formation of foci. Dimethyl fumarate, fumaricacid, genistein, piroxicam, simethicone, sodium suramin andsulindac reduced the yield of AOM induced foci of aberrant cryptswith genistein being the most potent. Only piroxicam of thisgroup has previously been shown to inhibit colon cancer, whilethe rest have yet to be evaluated. Ibuprofen did not inhibitthe formation of foci, although it has been reported to inhibitAOM-induced colon cancer in rats. Piroxicam and sulindac appearedto reduce preferentially hexosaminidase-negative foci of aberrantcrypts, compared with those of apparently normal morphology.The AOM-induced foci of aberrant crypts assay appears suitablefor screening chemicals for chemopreventive action.     

Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats

Omeprazole is a proton pump inhibitor, a widely used drug to treat ulcers and gastroesophageal refluxdisease. We have evaluated colon cancer chemopreventive properties of omeprazole using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats and analyzed cell growth inhibition and apoptosis induction in human colon cancer cells. Five-week-old male F344 rats were fed a control or experimental diet containing two doses of omeprazole (200 and 400?ppm). After one week, all animals were s.c. injected with AOM (15?mg/kg body weight, once weekly for two weeks). Rats continued on experimental diets for seven more weeks before being sacrificed. Colons were histopathologically evaluated for ACF. Human colon cancer HCT-116 and HCA-7 cells treated with omeprazole were evaluated for different markers associated with proliferation and apoptotic markers using Western blot technique. Rats fed with 200 and 400?ppm of omeprazole significantly suppressed total colonic ACF formation (~30%, P<0.001) and showed significant suppression of multi-crypt foci (~30-50%, P<0.05-0.001). Omeprazole produced significant dose-response effects on inhibition of multi-crypt foci (≥4). Omeprazole treatment in human colon cancer cell lines HCT-116 and HCA-7 cells resulted in induction of p21waf1/cip1 and decreased the expression of anti-apoptotic proteins Bcl-2, Bcl-XL and survivin in a dose-dependent manner. Anticancer properties observed in colon cancer cell lines suggest that omeprazole may induce key signaling molecules of antiproliferation and inhibition of anti-apoptotic proteins.     

Polyethylene-glycol, a potent suppressor of azoxymethane-induced colonic aberrant crypt foci in rats.

Bulking fibers and high water intake may decrease colon carcinogenesis in rats, and the risk of colorectal cancer in humans. We speculated that a non-fermented polymer, polyethylene-glycol (PEG) 8000, which increases stool moisture, might protect rats against colon carcinogenesis. Thirty female F344 rats were given a single injection of azoxymethane (20 mg/kg), and 7 days later randomized to AIN76 diets containing PEG (to provide 3 g/kg body wt/day), or no PEG (control). Diets were given ad libitum for 105 days, then colon carcinogenesis was assessed by the aberrant crypt foci (ACF) test. ACF were scored blindly by a single observer. Dietary feeding of PEG almost suppressed ACF larger than one crypt, and strikingly decreased the total number of ACF per rat. PEG-fed rats had 100 times less large ACF than controls (0.8 and 83 respectively, P = 0.00001). PEG-fed rats had 20 times less total ACF than control (six and 107 ACF/rat, respectively; P < 0.0001). Two treated rats had no detectable ACF. PEG is 10 times more potent than other chemopreventive agents in this model. Since PEG is generally recognized as safe, its cancer-preventive features could be tested in humans.     

Polyethylene-glycol suppresses colon cancer and causes dose-dependent regression of azoxymethane-induced aberrant crypt foci in rats.

Dietary polyethylene-glycol (PEG) 8000, a nonfermented polymer laxative, strongly suppresses azoxymethane-induced aberrant crypt foci (ACF) in the colon of rats, as shown in a previous study (D. E. Corpet et al., Carcinogenesis (Lond.), 20: 915-918, 1999). In the present study, we tested the effect of PEG administered during either initiation or postinitiation, the dose-response effect of PEG, the regressive effect of PEG on established ACF, and the preventive effect of PEG on colon cancers in rats. The general design was to initiate carcinogenesis in F344 rats by a single injection of azoxymethane (20 mg/kg) and to randomize the animals 7 days later to AIN-76 diets containing 5% PEG or no PEG (control). At termination, ACF and tumors were scored blindly by a single observer. The administration of 5% PEG for 32 days to groups of 10 female rats in either food or drinking water reduced the number of ACF by a factor of 8 (P = 0.0002) and reduced the number of large ACF by a factor of 20-30 (P = 0.002). No protection was afforded when PEG was given only during the initiation phase. Diets containing 0%, 0.5%, 2%, or 5% PEG fed for 35 days to four groups of male rats inhibited ACF in a dose-dependent manner (P < 0.0001). The administration of a 5% PEG diet for 41 days, starting 42 days after carcinogen injection, led to a 73% decrease in the number of ACF (P < 0.0001). Dietary PEG thus caused the regression of established ACF. Macroscopic tumors were evaluated by histology in rats that had been fed a high-fat diet containing cooked casein to promote tumor growth for 81 days. In this accelerated model of carcinogenesis, dietary PEG suppressed the occurrence of colon adenomas and carcinomas: the incidence of tumors decreased from 70% to 10% (P = 0.005); and the multiplicity decreased from 2.1 to 0.1 tumor(s)/rat (P = 0.003). No cancer was detected in the PEG-fed rats. Taken together, these results suggest that PEG could be a potent anticancer agent in the postinitiation phase of carcinogenesis. Because PEG is a substance that is generally recognized as safe (GRAS list, Food and Drug Administration), its cancer-preventive features could be tested in humans.     

Dietary conjugated linolenic acid inhibits azoxymethane-induced colonic aberrant crypt foci in rats.

The modifying effects of dietary feeding of conjugated linolenic acid (CLN) isolated from the seeds of bitter gourd (Momordica charantia) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats to predict its possible cancer chemopreventive efficacy. The effect of CLN on the proliferating cell nuclear antigen (PCNA) index in colonic ACF was also examined. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks to induce ACF. They also received the experimental diet containing 0.01%, 0.1% or 1% CLN for 5 weeks, starting one week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (108 +/- 21/rat) at the end of the study (week 4). Dietary administration of CLN caused a significant reduction in the frequency of ACF: 87 +/- 14 (19.4% reduction, P < 0.05) at a dose of 0.01%, 69 +/- 28 (36.1% reduction, P < 0.01) at a dose of 0.1% and 40 +/- 6 (63.0% reduction, P < 0.001) at a dose of 1%. Also, CLN administration lowered the PCNA index and induced apoptosis in ACF. These findings might suggest possible chemopreventive activity of CLN in the early phase of colon tumorigenesis through modulation of cryptal cell proliferation activity and/or apoptosis.     

SHORT COMMUNICATION: Piroxicam-induced regression of azoxymethane-induced aberrant crypt foci and prevention of colon cancer in rats

Piroxicam has been shown to prevent azoxymethane (AOM)-inducedaberrant crypt foci and colon cancer in rats. In this communicationwe evaluate whether piroxicam can also cause regression of precancerouslesions identified as aberrant crypt foci, thus preventing theoccurrence of cancer. Male Fischer-344 rats were administered0.125g/kg piroxicam in theirdiet starting either 1 week priorto or 12 weeks after a single subcutaneous injection of AOM(30 mg/kg body wt). The yield of aberrant crypt foci and ofcolon adenomas and adenocarcinomas was determined at 5, 12,27 and 37 weeks after administering the AOM respectively. Whenpiroxicam was administered starting 1 week prior to AOM theyield of aberrant crypt foci at the three initial time pointswas reduced. When the administration of piroxicam was delayeduntil 12 weeks afterAOM the yield of aberrant crypt foci wasreduced from 53.8±8.1 foci/colon at 12 weeks to 11.1±2.0at 27 weeks. At 37 weeks after administering AOM the yield ofcolon tumors was 0.59±0.11 tumors/animal, while in ratsadministered piroxicam beginning either 1 week prior to or 12weeks after AOM the yield was similarly reduced to 0.14±0.07and 0.17±0.07 tumors/animal respectively. Thus piroxicamwas demonstrated not only to prevent, but also to cause regressionof aberrant crypt foci, both of which were associated with theprevention of colon tumors.     

Synergistic suppression of azoxymethane-induced foci of colonic aberrant crypts by the combination of {beta}-carotene and perilla oil in rats

The modulating effect of the combined dietary feeding of ß-caroteneand perilla oil, which is rich in     

Reovirus decreases azoxymethane-induced aberrant crypt foci and colon cancer in a rodent model

Reovirus type 3 Dearing has demonstrated oncolytic efficacy in vitro and in vivo against a variety of cancer cell lines, tumor xenografts and syngeneic cancer models. In this study, we investigated the effectiveness of reovirus against aberrant crypt foci (ACF) and colon cancer induced by the carcinogen azoxymethane (AOM) in an immunocompetent rat model. Sprague-Dawley rats received 15 mg/kg AOM intraperitoneally once per week for 4 weeks and reovirus was administered rectally once a week for 5 weeks starting 20 weeks after the last dose of AOM. Two weeks after completion of reovirus therapy, animals were examined for tumor burden in the colon and other tissues. Reovirus-treated animals showed a decrease in total ACF numbers (P=0.014), in large ACFs (P=0.0069) and in tumor number (P=0.03) compared to vehicle-treated animals. Fewer obstructing tumors in the colon (P=0.07) and duodenum (P=0.03) and reduced hepatic metastases were also noted. In addition, a tumor cell line derived from hepatic metastases was found to be susceptible to reovirus in vitro. Our results show that repeated rectal reovirus administration had some efficacy in the treatment and prevention of AOM-induced ACFs, colon cancers and metastases.     

Induction of apoptosis by sulindac in azoxymethane-induced possible colonic premalignant lesions in rats.

We have reported that beta-catenin-accumulated crypts (BCAC), which do not have the appearance of aberrant crypt foci (ACF) are possible colonic premalignant lesions in rats. Suppression of the occurrence and advancement of such lesions should have critical relevance to cancer prevention. This study examined whether sulindac, a chemopreventive nonsteroidal anti-inflammatory drug is able to induce apoptosis in such premalignant lesions. At 6 weeks of age, rats groups 1 - 3 were given azoxymethane (AOM) (15 mg/kg-body weight) once weekly for 3 weeks. Two groups were given sulindac in the diet (200 and 400 ppm), starting at 9 weeks of age. The rats were sacrificed at the termination, and the colons were carefully examined. The incidence and crypt multiplicity of BCAC and ACF were significantly less than those of the control group. The effect of sulindac on the expression of BCAC was greater than that on ACF. Exposure to sulindac significantly increased the apoptotic index (terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL)-positive cells) in BCAC. However, no significant increase of the index was found in the case of ACF. These results suggest that the chemopreventive effect of sulindac in rats is related to the induction of apoptosis in premalignant lesions. Our results also provide additional evidence that BCAC are premalignant lesions in colon carcinogenesis in rodents.     

S-adenosyl L-methionine inhibits azoxymethane-induced colonic aberrant crypt foci in F344 rats and suppresses human colon cancer Caco-2 cell growth in 3D culture

S-adenosyl L-methionine (SAM) is a universal methyl group donor to various intermediary metabolites, hormones, proteins, neurotransmitters, phospholipids and nucleic acids. Deficiency of folate, which plays a role in the synthesis of SAM leads to increased risk for colon cancer. This study tested the effectiveness of SAM supplementation in protecting against azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. We also tested the effect of SAM on cyclooxygenase-2 (COX-2) in a macrophage cell line. Further, we developed a 3-D culture model using Caco-2 cells to test the effect of SAM on tumor spheroid size and number. Groups of rats were given the experimental diet containing either 0-, 400- or 800-ppm SAM, 1 week before the first AOM injection and continued until 8 weeks. In the control group, AOM produced a substantial number of aberrant crypt foci (ACF) (96 +/- 8). Dietary administration of SAM significantly reduced the number of total ACF (400 ppm SAM, 68 +/- 7.3, p < 0.01 and 800 ppm SAM, 57 +/- 7.1, p < 0.001). SAM significantly decreased AOM-induced colonic multicrypt foci in a dose-dependent manner. Suppression of Lipopolysaccharide (LPS) induced COX-2 protein expression was observed in a RAW264.7 cell line. We established growth of Caco-2 cells as spheroids, in a 3D matrix of collagen and matrigel. Treatment with SAM decreased both size and number of spheroids in a dose-dependent manner (p < 0.0001). These observations demonstrate for the first time that SAM can reduce the occurrence of ACF in AOM treated male F344 rats and suppress formation of human tumor spheroids and expression of COX-2.     

Inhibition of azoxymethane-induced experimental colon carcinogenesis in Wistar rats by 6-hydroxydopamine.

The effects of 6-hydroxydopamine (6-OHDA) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on norepinephrine (NE) concentration in the colon wall and the labelling index of the colon mucosa were investigated in Wistar rats. Rats received sub-cutaneous (s.c.) injections of AOM once a week for 10 weeks, and throughout 35 weeks were also given intraperitoneal (i.p.) injections of 6-OHDA. Prolonged administration of 6-OHDA was found to cause a significant reduction in the incidence and number of colon tumors. However, it had no influence on the histological features or depths of involvement of colon tumors and/or adenocarcinomas. Its administration also caused significant decreases in the NE concentration in the colon wall and in the labelling index of the colon mucosa. Our findings indicate that 6-OHDA has a protective effect against colon carcinogenesis, and that the activity of the sympathetic nervous system may have an important influence on colon carcinogenesis.     

Preventive effects of chrysin on the development of azoxymethane-induced colonic aberrant crypt foci in rats

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.     

The effect of an oral administration of Lactobacillus casei strain shirota on azoxymethane-induced colonic aberrant crypt foci and colon cancer in the rat

The preventive effect of oral administration of viable Lactobacillus casei strain Shirota (LcS) on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) and colon cancers in the rat was investigated. The study consisted of two experiments; in a short-term experiment (Exp-I), the inhibitory effect of 8- and 12-week treatments with LcS. Forty rats each received weekly a subcutaneous injection of AOM at a dose of 15 mg/kg of body weight for 5 weeks. Eight and twelve weeks after the start of the carcinogen treatment, each subgroup of rats were sacrificed, and the colon and the mesenteric lymph nodes (MLN) were removed. The number of ACFs and the surface marker of lymphocytes derived from the MLN were investigated. The large ACF (those comprising four or more aberrant crypts per focus) had significantly decreased in the rats which had consumed the LcS diet. And oral administration of viable LcS significantly recovered CD8 positive lymphocytes to the levels in the control group. In a long-term experiment (Exp-II), 30 rats each received weekly a subcutaneous injection of AOM at a dose of 7. 4 mg/kg of body weight for 10 weeks. Twenty-five weeks after the start of the carcinogen treatment, each subgroup of rats were sacrificed, and the colon were removed. The number and incidence of colon cancers were investigated. The number of rats with colon cancers and the number of colon cancers per rat, were significantly decreased in the rats which had consumed the LcS diet. LcS inhibited chemically-induced colon carcinogenesis in the rat. CD8 positive T lymphocytes may play a key role in the preventive effect against colon carcinogenesis.     

Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings

In the present study a methodological approach is taken which quantitates aberrant dysplastic crypts in the unsectioned murine colon. C57BL/6J or CF1 female mice (7-8 weeks old) were injected (i.p.) with azoxymethane (5 mg/kg body wt./week) for 4 weeks. Their colons were excised, cut open on the median axis and fixed flat in buffered formalin. Unsectioned colons were stained with methylene blue. The mucosal side was examined under a light microscope. The aberrant crypts, which are larger and have a thicker epithelial lining, were easily visualized using X 4 or X 10 objectives. CF1 mice, which are more sensitive to developing colon tumors, had a higher number of aberrant crypts/colon than their less sensitive counterparts, C57BL/6J mice (5.0 +/- 0.7 vs. 2.4 +/- 0.7). The usefulness of this observation as a possible measure of neoplastic events is discussed in the animal and human situation.     

Suppression of azoxymethane-induced colon cancer development in rats by dietary resistant starch

Resistant starch is a complex carbohydrate that reaches the colon where it can be fermented by the colonic microflora resulting in production of short chain fatty acids (SCFA), in particular butyrate. RS effects on colorectal tumourigenesis are contrasting and protection remains controversial. Butyrate has an important role as the preferred metabolic fuel and regulator of colonocyte proliferation, differentiation and apoptosis and may play a role in cancer prevention. Thus variation in butyrate production from different substrates might explain the variation in effect of RS. This study evaluated the hypothesis that feeding dietary resistant starch (as high amylose maize starch) would protect against azoxymethane (AOM)-colon carcinogenesis and favourably influence the colonic luminal environment. Male Sprague-Dawley rats (n = 90) were provided one of three diets: Control (without added dietary fibre or RS), 10% HAS (contained 100 g/kg raw high amylose maize starch) or 20% HAS (contained 200 g/kg high amylose maize starch). Rats were fed their experimental diets for four weeks after which they were injected with AOM (15 mg/kg) during the fifth and six week. Colons were resected (25 weeks post second injection) for evaluation of tumour formation, apoptosis, proliferating cell nuclear antigen (PCNA) labelling index and short chain fatty acid levels. Feeding resistant starch significantly reduced the incidence (p < 0.01) and multiplicity (p < 0.05) of adenocarcinomas in the colon compared to the Control diet. Both doses of HAS resulted in similar protection against colon tumourigenesis. Feeding RS significantly increased total SCFA concentrations, including butyrate in the distal colon. Apoptosis (p < 0.01) was also enhanced while PCNA labelling index was reduced (p < 0.01) in the distal colon with resistant starch feeding. The protective effect of consumption of RS as dietary high-amylose cornstarch against colon cancer development appears to be related to active fermentation in the colon, particularly through production of butyrate.     

Termination of piroxicam treatment and the occurrence of azoxymethane-induced colon cancer in rats

Piroxicam has been shown to prevent azoxymethane (AOM)-induced colon cancer when administered during the promotion/ progression phase. The requirement for continued treatment with piroxicam in order to maintain prevention of colon cancer was investigated. Male F344 rats were administered 15 mg/kg AOM at 7 and 8 weeks of age and started to receive piroxicam (200 mg/kg) in their diet at 11 weeks after the second dose of AOM. Piroxicam was removed from the diet of some of the rats at weeks 19 and 28 and the animals were held until week 47. Other rats continued to receive piroxicam until sacrificed at week 47. Treatment with piroxicam from week 11-47 reduced the yield of colon tumors. When treatment was terminated at week 19 or 28 the yield of tumors at week 47 was not reduced. Within 1 week of the start of piroxicam treatment, the number of aberrant crypt foci (ACF)/animal was decreased. Termination of treatment resulted in the recurrence of ACF. Apoptosis in adenomas was increased when piroxicam treatment was continued to week 47 but not when treatment was terminated earlier at week 19 or 28. The proliferating cell nuclear antigen-labeling index in adenomas was not affected by piroxicam even when treatment was from week 11 to 47. In summary, termination of treatment resulted in the occurrence of ACF and colon cancer indicating that prevention by piroxicam was reversible. Furthermore, enhancement of apoptosis and not decreased cell proliferation correlated with prevention of colon cancer.     

P53 gene mutation increases progastrin dependent colonic proliferation and colon cancer formation in mice

Transgenic mice overexpressing human progastrin (hGAS) show colonic crypt hyper-proliferation and elevated susceptibility to colon carcinogenesis. We aimed to investigate effects of p53 mutation on colon carcinogenesis in hGAS mice. We show that introducing a p53 gene mutation further increases progastrin dependent BrdU labeling and results in markedly elevated number of aberrant crypt foci (ACF) and colonic tumors. We demonstrate that hGAS/Lgr5-GFP mice have higher number of Lgr5+ colonic stem cells per crypt when compared to Lgr5-GFP mice indicating that progastrin changes crypt biology through increased stem cell numbers and additional p53 mutation leads to more aggressive phenotype in this murine colon cancer model.