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PubMed1998

The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers.

Continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the relative risk of colorectal cancer in humans and decreases tumor yield in rodents treated with carcinogens. One well documented target for NSAIDs is prostaglandin endoperoxide synthase (cyclooxygenase) and two isoforms of this enzyme have been identified, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX enzymes produce eicosanoid products, some of which have recently been shown to activate transcription mediated by the nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARgamma), whose expression is largely restricted to adipose tissue. The present study was undertaken to determine if PPARgamma was expressed in colonic tumors. PPARgamma messenger RNA (mRNA) and protein levels were assayed in colonic tumors and normal adjacent mucosa, as well as in a variety of human colon cancer cell lines. There was a marked increase in PPARgamma RNA levels in four out of four of the colonic tumors compared to paired normal mucosa, where little expression of PPARgamma was detected. Western blotting analysis showed that PPARgamma protein was expressed in four out of five colonic tumor samples. PPARgamma was also expressed in a subset of polyps, and in certain human colon cancer cell lines as well. Additionally, we were able to demonstrate that an eicosanoid, 15 deoxy-delta12,14 PGJ2, transactivated transcription of a PPRE-driven promoter in CaCo-2 cells. Thus, we have shown that PPARgamma gene and protein expression is elevated in rodent colon tumors, in selected human colon cancer cell lines and that the PPARgamma receptor is functional in CaCo-2 cells. Since PPARgamma is a ligand-modulated transcription factor, it may provide a novel target for chemopreventive strategies for colorectal cancer.

Adenocarcinoma↗
PubMed1998

Dietary fish oil inhibits the expression of farnesyl protein transferase and colon tumor development in rodents.

Although epidemiological and experimental studies indicate a strong relationship between different dietary fats and risk of colon cancer, the modulating effects of these nutritional factors at the molecular level are not fully elucidated. Activated ras genes have been implicated in the etiology of many human malignancies, including colon cancer. It is well established that the transforming ability of ras-p21 depends on its correct localization in plasma membrane. We have previously demonstrated that ingestion of a relatively higher amount of dietary fish oil leads to reduced plasma membrane levels of ras-p21 with concomitant increase in its cytoplasmic contents during the promotion and progression phases of chemically-induced colon tumorigenesis. In this follow-up experiment, we have found that intake of a high amount of corn oil, one of the most widely used fats in the American diet, enhances the expression of farnesyl protein transferase (FPTase). This enzyme catalyses farnesylation of ras precursors in a critical step during post-translational modification of ras oncoproteins, thereby enabling their anchorage to plasma membrane. In contrast, consumption of high amounts of fish oil, which is rich in omega-3 polyunsaturated fatty acids, reduces the levels of FPTase expression, thus inhibiting post-translational processing of ras precursors resulting in decreased ras function both in colonic mucosa as well as in colon tumors. These results correlate with increased incidence and multiplicity of grossly visibly colon tumors in carcinogen-treated animals fed a high corn oil diet versus decreased incidence and multiplicity of colon tumors in their counterparts fed the high fish oil diet. This dietary inhibition of FPTase may have a practical chemopreventive potential.

Alkyl and Aryl Transferases↗
PubMed2005

Impact of physical activity on intestinal cancer development in mice.

Observational epidemiology supports the hypothesis that variation in diet and other lifestyle exposures accounts for a large part of the variation in incidence of colorectal cancer (CRC). Physical inactivity is associated strongly with enhanced CRC risk, but no human intervention studies have shown causality. This paper reviews data from all available studies of the effects of exercise interventions on intestinal neoplasia using rat and mouse models. All 5 published studies of effects of increased physical activity (both forced and voluntary) using carcinogen-treated rat models show strong protection against CRC by greater physical activity. In contrast, there is little convincing evidence of reduced intestinal neoplasia after increased physical activity in the 3 published studies using Apc(Min) mice (which develop multiple intestinal polyps spontaneously) although the nature and amounts of physical activity imposed in rats and mice were similar. Major differences in protocol between the 2 groups of studies are that the rat studies were much longer (at least 20 wk and in most cases 38 wk compared with < or =9 wk for the mouse studies) and the primary endpoint was colorectal carcinoma (rats) rather than small bowel adenomas (mice). The epidemiological evidence for protection against adenoma formation by increased physical activity is weaker than that for carcinoma. The limited evidence available suggests that, compared with rats, mice may show a greater compensation for energy expenditure in exercise through reduction in nonexercise physical activity, thus ameliorating effects. The resulting smaller effects on body weight and body fatness may limit changes in intestinal neoplasia in Apc(Min) mice.

1,2-Dimethylhydrazine↗
PubMed1995

Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage by green tea extract in rat.

Following subcutaneous injection of 1,2-dimethylhydrazine (DMH), which is carcinogenic to rat colon and liver, to Sprague-Dawley rats, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) was observed in the DNA of colonic mucosa and liver. The 8-OHdG formation reached the maximal level at about 24 h after the DMII injection. On the other hand, no increase of 8-OHdG was observed in the DNA of the kidney. Drinking green tea extract (GTE) for ten days prior to the DMH injection significantly inhibited the formation of 8-OHdG in the colon. These findings demonstrate that DMH causes oxidative damage to the DNA of its target organ, and that GTE protects colonic mucosa from this oxidative damage.

1,2-Dimethylhydrazine↗
PubMed2005

In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy.

BACKGROUND: Mouse models of colitis and cancer are indispensable for our understanding of the pathogenesis of these diseases. In the past, mice had to be sacrificed in order to analyse colitis activity and tumour development. We have developed a safe method for high resolution endoscopic monitoring of living mice. METHODS: Mice developing colitis or colonic tumours were anaesthetised using avertine and repeatedly examined by endoscopy. A novel miniendoscope (1.9 mm outer diameter), denoted Coloview, was introduced via the anus and the colon was carefully insufflated with an air pump before analysis of the colonic mucosa. An extra working channel allowed the introduction of biopsy forceps or injection needles as well as surface staining with methylene blue in order to visualise the surface of the crypts and the pit pattern architecture. RESULTS: Endoscopic pictures obtained were of high quality and allowed monitoring and grading of disease. Scoring of colitis activity as well as tumour size and growth was possible. In addition, pit pattern analysis using chromoendoscopy permitted discrimination between inflammatory and neoplastic changes. Biopsies yielded enough tissue for molecular and histopathological analyses. CONCLUSIONS: In summary, chromoendoscopy in mice allows monitoring of the development of colitis and colon cancer with high resolution. Manipulations such as local injection of reagents or taking biopsies can be performed easily.

Animals↗
PubMed1999

Morphological and morphometric studies of the splenic antitumor immune response, elicited by liposome-covered soluble p53 kDa antigen, in chemically-induced rat colon cancer.

We evaluated the splenic morphometric changes in rats treated with carcinogen to study development of anti-cancer immune response. When liposome-covered soluble 53 kDa antigen (s53) was injected into these rats, significant tumor-suppression was seen and the percentage of tumor-free animals rose from 15.4% in non-vaccinated rats to 53.8%. In the spleens of carcinogen treated rats that did not develop tumors, activity of B lymphocytes increased significantly. This was manifested by the expansion of the germinal centers to 50.9% of the follicular area reflecting depletion of B cells, and the decrease of the mantle layer to 48.9% of the follicles. A similar picture was seen with T lymphocytes: the area of the marginal zone decreased to 55.2% of the T zone of the white pulp, and that of the periarterial lymph sheaths (PALS) to 33.6%. In tumor-bearing rats features of the immune decompensation were seen: the germinal centers increased to 96.5% of the follicular area, and the mantle layer and PALS decreased significantly. Vaccination prevented these effects, especially in tumor-bearing rats: the PALS occupies 30.4% of the white pulp and the marginal zone 56.1%, and the mantle layer occupied 58.1% of the follicular zone. Similar changes were found in vaccinated rats without tumors reflecting the compensatory character of the immune reaction in vaccinated rats. In conclusion, we found that treatment with carcinogen followed by vaccination with the s53-liposomes complex stimulated the activity of the splenic B, and to a lesser degree the T systems.

Animals↗
PubMed2000

Cancer immunomodulation by carbohydrate ligands for the lymphocyte receptor NKR-P1.

Natural killer (NK) and T cells express a superfamily of proteins with structural features of C-type lectins. Recombinantly prepared soluble form of rat NKR-P1 (CD161) recognized carbohydrate GalNac and GlcNac moieties. Ganglioside GM2 and heparin related-IS oligosaccharides representing the high affinity ligands for this receptor, increased the sensitivity of targets for killing by the rat effectors isolated from blood and spleen in vitro. Based on these results, we investigated in vivo the possible therapeutic effect of GM2 and IS carried by liposomes during induced rat colorectal carcinogenesis. The reduction of cancer incidence versus the controls (50% vs 88.88%), approached the 5-fluorouracil treatment (41.66%).

Animals↗
PubMedDate not supplied

Preventive effect of fermented brown rice and rice bran against colon carcinogenesis in male F344 rats.

Epidemiological and preclinical studies demonstrate that nutrition plays an important role in the etiology of cancer. It has been reported that rice components, especially rice germ plays a key role in prevention of cancer. The experiments described here examined the potential anticancer properties of brown rice fermented by Aspergillus Oryzae (FBRA) in male F344 rats using inhibition of the formation of azoxymethene (AOM) induced aberrant crypt foci (ACF) and tumors in the colon as the measure of preventive efficacy. The agent was administered at 2.5 and 5% levels in the diet during the initiation phase (during and until 1 week after carcinogen treatment) and/or post-initiation phase (beginning 1 week after carcinogen treatment) of carcinogenesis. In the ACF and tumor studies, rats were sacrificed 5 or 40 weeks after the initiation of AOM treatment (15 mg/kg body weight, once weekly for 3 weeks), respectively. Colonic ACF and tumors were evaluated histopathologically. Administration of 2.5 and 5% FBRA in the diet continuously during initiation and post-initiation period significantly inhibited the ACF formation in rats treated with AOM, compared with rats treated with AOM alone (99+/-24.1 and 79+/-18.4 vs. 139.5+/-27.7, respectively). In addition, administration of 5% FBRA in the diet during the post-initiation phase significantly suppressed the incidence (44 vs.18%) and multiplicity (0.93+/-0.96 vs. 0.18+/-0.40) of colon adenocarcinomas as compared to those given the control diet. In addition, 5% FBRA in the diet during post-initiation phase caused significant inhibition of cell proliferation in the colonic mucosa as compared to the group fed the control diet (81% reduction, p<0.05). These observations demonstrated for the first time that FBRA inhibits colon tumor development in rats, and suggest that it is a promising dietary supplement for prevention of human colon cancer.

Animals↗
PubMed1992

Dietary fiber-mediated mechanisms in carcinogenesis.

Dietary fiber may affect the development of cancers of the gastrointestinal tract and the breast. The biological intermediates studied most have been fecal bile acids; both human and animal studies suggest a tumor-promoting role of bile acids in the development of colon tumors, although there are conflicting data from human studies. Short-chain fatty acids are major fermentation products of bacterial degradation of dietary fiber. If short-chain fatty acids explained the tumor-inhibiting properties of dietary fiber, the readily fermentable fibers such as guar and pectin would be more protective than cellulose and wheat bran, which has not been observed. Because these two hypotheses do not adequately explain modulation of tumor growth by dietary fiber, investigation of other intermediates is indicated. These include physical characteristics of the feces, such as abrasiveness; intestinal microflora; aqueous-phase bile acids, which may represent the bioavailable pool; alterations in mucins; mutagenicity of intestinal contents; alterations in mucosal cytokinetics; activities of enzymes, such as ornithine decarboxylase or aryl hydrocarbon hydroxylase; neurogenic effects caused by changes in intestinal bulk or short-chain fatty acids; gut hormones or other peptide growth factors (local or systemic); enterohepatic circulation of hormones; transit time; pH; or decreased availability of total dietary energy.

Animals↗
PubMed1991

[Experimental models for hepatic metastases from colorectal tumors].

Over recent years, the interest in the development of experimental models of colorectal liver metastases has increased due to the need for new adjuvant therapies to improve the treatment of both colorectal cancer and liver metastases. The induction of colon cancer by carcinogens in the rat with spontaneous liver metastases fairly closely mimicks the natural history of colon cancer but a low yield of both colonic cancer (less than 50%) and liver metastases (approx. 25%) is obtained after 6 months of latency. Direct intraportal injection of cells derived from a colon carcinoma cell line is the experimental model most often used. Although it bypasses the natural history of cancer this simple model produces up to 100% of liver metastases 6 weeks after injection of cells. These two models have been used for several studies of liver metastases concerning their morphology, their modulating factors and their vascularisation. They have been used to test new adjuvant therapies for colorectal cancer.

Animals↗