Dietary omega-3 fats reduce proliferation and tumor yields at colorectal anastomosis in rats.

BACKGROUND & AIMS: Colorectal anastomoses show increased mucosal crypt cell proliferation rates (CCPRs) and often form the site for tumor recurrence after resection of colorectal cancer. The aim of this study was to assess the effects of a 20% omega-3 fat diet on CCPRs and anastomotic tumor formation compared with an isocaloric 20% saturated fat diet in experimental colorectal cancer. METHODS: One hundred sixty male Wistar rats were administered azoxymethane or saline for 6 weeks, after which a colonic anastomosis or sham operation was performed. CCPR, mucosal fatty acids, and tumor yield were analyzed at the anastomosis and proximal and distal colon sites at 15 and 23 weeks. RESULTS: Diet, carcinogen treatment, and surgery all had significant effects on CCPR with omega-3 fats producing the lowest CCPR at all sites. There were fewer tumors (P < 0.02), including a marked reduction of anastomotic tumors in omega-3 fat-fed animals that was associated with a significant reduction of arachidonic acid in mucosal and tumor lipids. CONCLUSIONS: Dietary omega-3 fat significantly reduced colonic CCPR and tumor yield, including at the site of anastomosis. Dietary omega-3 fats may be of value to patients after colorectal resection and anastomosis for cancer and warrant further testing.

Activities of phospholipase A2 and diacylglycerol lipase are increased in human colorectal cancer.

Experimental, clinical and epidemiological studies have implicated arachidonic acid and its metabolites as important mediators in colorectal carcinogenesis. Although arachidonic acid levels are increased in tumour membrane lipids, its availability for metabolic processes is not known. The activities of phospholipase A2 (PLA2) and diacylglycerol lipase therefore were assessed in tumour and normal mucosal specimens from 20 patients with colorectal cancer using 14C-radiolabelled substrates. The median (interquartile range) PLA2 activity was increased in tumour tissue (10.5 (6.0, 18.5) pmol arachidonic acid mg-1 h-1) compared with that in normal mucosa (5.6 (2.5, 8.5) pmol arachidonic acid mg-1 h-1) (P < 0.001, Wilcoxon signed rank test). Activity of diacylglycerol lipase was also greater in tumoral tissue (47.4 (21.6, 82.1) pmol arachidonic acid mg-1 h-1) than in mucosa (19.1 (9.4, 42.9) pmol arachidonic acid mg-1 h-1) (P < 0.005). There was no correlation between either PLA2 or diacylglycerol lipase activity and myeloperoxidase activity, suggesting that these increases were not directly attributable to tumour inflammatory cell infiltrate. Augmentation of arachidonic acid release in colorectal tumours may have implications for therapy.

Lipid peroxidation and prostaglandins in colorectal cancer.

Dietary fat, arachidonic acid metabolism and lipid peroxidation have all been implicated in colorectal carcinogenesis. Fatty acids, prostaglandins (PGE2, PGF2 alpha) and malondialdehyde (MDA), the stable end-product of lipid peroxidation of polyunsaturated fatty acids (PUFAs), were studied in paired tumour and normal mucosa of 20 patients with colorectal cancer. Levels of arachidonic acid and total PUFAs were increased in the phospholipid fraction of tumours (P < 0.05). Levels of PGE2 and MDA were also higher in tumours (P < 0.001) and there was a significant correlation between MDA and PGE2 concentrations (rs = 0.69, P < 0.01). In contrast to previously reported in vitro studies, this work suggests that lipid peroxidation may be enhanced in human colorectal tumours. As PGE2 and MDA have been shown to be involved in carcinogenesis, these may be considered potential therapeutic targets for preventing or treating colorectal carcinoma.

Oestrogen and progesterone receptors in colorectal cancer and human colonic cancer cell lines.

Receptors for oestrogen (ER) and progesterone (PR) were assayed in tissue from 17 patients with colorectal cancer and five colonic cancer cell lines using enzyme immunoassays. ERs and PRs were detected in 15 and 17 cancers respectively, although the levels detected were low: median (range) ER 1.3 (0-11.3) and PR 3.9 (0.3-10.2) fmol per mg protein. These values were not significantly different from median (range) levels of ER (1.1 (0.6-3.0) fmol/mg) and PR (1.9 (0.5-3.2) fmol/mg) detected in normal mucosa. There were significant positive correlations between the levels of ER and PR for cancer tissue (tau = 0.56, P < 0.005; r(log transform) = 0.68, P < 0.003; n = 17) but not for mucosa, and between levels of ER in cancer tissue and mucosa (tau = 0.55, P < 0.05; r(log transform) = 0.70, P < 0.025; n = 10) but not between the corresponding PR values. In maintenance media, which contained phenol red and unstripped fetal calf serum, the median (range) concentration of ER was 1.9 (1.2-10.4) fmol/mg and that for PR 24.3 (9.1-63.2) fmol/mg in the five cell lines studied (HT-29, LS174T, SW620, LoVo, COLO 320DM). The addition of oestradiol (10 nmol/l) to phenol red-free medium containing 5 per cent dextran-coated charcoal-treated fetal calf serum had little effect on the concentration of ERs or PRs in SW620, LoVo and COLO 320DM cells after 7 days' culture. It is concluded that ERs and PRs are expressed in malignant and normal colonic mucosa. ERs appear to be a feature of the colonic mucosa rather than the malignant process, but in carcinoma may regulate synthesis of PRs, suggesting a degree of oestrogen responsiveness.

Faecal unconjugated bile acids in patients with colorectal cancer or polyps.

The unconjugated faecal bile acid profiles of 14 patients with colorectal cancer, nine patients with polyps and 10 controls were compared using gas liquid chromatography, controlling for such confounding variables as cholecystectomy, gall stones and hepatic function. Patients with adenomatous polyps had a higher concentration of faecal bile acids (5.23 mumol/g, 2.16-13.67 (median, range) v 1.96, 0.91-6.97; p = 0.016) lithocholic acid (2.41, 0.88-3.22 v 1.07, 0.38-2.03; p = 0.013) and total secondary bile acids (5.23, 2.16-13.4 v 1.96, 0.73-6.63; p = 0.02) compared with control subjects. Patients with colorectal cancer had an increased (p = 0.029) proportion of secondary faecal bile acids (mol%) compared with controls (100, 96.5-100 v 95.19, 81.73-100) and the ratios of the primary bile acids, cholic and chenodeoxycholic acid, to their respective derivatives (secondary bile acids) were significantly lower in cancer patients compared with control and patients with polyps (p = 0.034 to 0.004). This study lends further support to the theory that bile acids may play a role in the development of polyps and colorectal cancer.