linoleic-acid and Papilloma

Several recent reports have suggested that peroxisome proliferator-activated receptors (PPARs) may be involved in the development of neoplasias in different tissue types. The present study was undertaken to determine whether PPARs play a role in skin physiology and tumorigenesis. In an initiation-promotion study, SENCAR mice treated topically with the PPARalpha ligands conjugated linoleic acid and 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy-14643) exhibited an approximately 30% lower skin tumor yield compared with mice treated with vehicle. The PPARgamma and PPARdelta activators troglitazone and bezafibrate, respectively, exerted little, if any, inhibitory activity. PPARalpha was detected in normal and hyperplastic skin and in papillomas and carcinomas by immunohistochemistry. In addition, PPARalpha, PPARdelta/PPARbeta, and PPARgamma protein levels were analyzed by immunoblotting in normal epidermis and papillomas. Surprisingly, the levels of all three isoforms were increased significantly in tumors as opposed to normal epidermis. In primary keratinocyte cultures, protein levels of PPARalpha and, to a lesser extent, PPARgamma were markedly increased when the cells were induced to differentiate with high-calcium (0.12 mM) conditions. In addition, we observed that Wy-14643 enhanced transcriptional activity of a peroxisome proliferator-response element-driven promoter in a mouse keratinocyte cell line. These results demonstrate that keratinocytes express functional PPARalpha, that PPARalpha may play a role in differentiation, and that ligands for PPARalpha are moderately protective against skin tumor promotion. We conclude that selective PPARalpha ligands may exert their protective role against skin tumor promotion by ligand activation of PPARalpha.

Topics: Animals; Anticarcinogenic Agents; Bezafibrate; Blotting, Western; Cell Differentiation; Cell Line; Chromans; Female; Keratinocytes; Linoleic Acid; Mice; Mice, Inbred SENCAR; Papilloma; Peroxisome Proliferators; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Skin; Skin Neoplasms; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Up-Regulation

The fatty acid derivative conjugated dienoic linoleate (CLA) has been shown to inhibit initiation and postinitiation stages of carcinogenesis in several experimental animal models. The goal of the present study was to determine the role of increasing levels of dietary CLA in mouse skin tumor promotion elicited by 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice were fed control (no CLA) diet during initiation, then switched to diets containing 0.0%, 0.5%, 1.0%, or 1.5% (wt/wt) CLA during skin tumor promotion by TPA. Body weights of mice fed 0.5%, 1.0%, or 1.5% CLA were similar to each other but were significantly lower (p < 0.05) than weights of mice fed no CLA (0.0%) throughout promotion. A reduction in papilloma incidence was observed in mice fed 1.5% CLA from Weeks 8 to 24 compared with mice fed diets containing 0.0-1.0% CLA (p < 0.05). Twenty-four weeks after tumor promotion was begun, diets containing 1.0% and 1.5% CLA inhibited tumor yield (4.94 and 4.35 tumors/mouse, respectively) compared with diets without CLA (0.0% CLA, 6.65 tumors/mouse, p < 0.05) or 0.5% CLA (5.92 tumors/mouse, p < 0.05). These data indicate that CLA inhibits tumor promotion in a manner that is independent of its anti-initiator activity. Further studies are warranted in identifying cellular mechanisms that are likely to be involved with the antipromoter effects of CLA.

Topics: Animals; Body Weight; Dietary Fats, Unsaturated; Female; Linoleic Acid; Linoleic Acids; Mice; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

Based on the biological activity of arachidonic acid metabolites, we hypothesized that alterations in the consumption of linoleic acid, the precursor to arachidonic acid, would result in a modification in tumor development when fed during the tumor promotion stage of the mouse skin initiation-promotion model. The effects of seven different levels of dietary linoleic acid (LA), supplied as corn oil in a 15% fat diet, on the incidence and rate of papilloma and carcinoma development were determined. SENCAR mice were placed on one of the experimental diets, containing 1.0, 3.6, 6.0, 7.9, 9.9, 12.5, or 15.0% corn oil, 1 week after initiation with 10 nmol of 7,12-dimethylbenz(a)anthracene and 3 weeks prior to the start of twice weekly promotion with 1 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA). At 15 weeks of TPA treatment there were significant differences in papilloma number among diet groups, such that an inverse correlation (r = 0.92) was observed between tumor number and level of corn oil; the lowest corn oil diet group had an average of 11.7 tumors/mouse, while the highest corn oil group had 5.4 tumors/mouse. However, there was little difference in tumor incidence among diet groups. A general relationship between diet and carcinoma incidence was also found, such that the highest corn oil diet group had the lowest carcinoma incidence. In an experiment performed with DBA/2 mice, the average number of papillomas/mouse at 17 weeks was 4.5 (1.0% corn oil), 5.6 (7.9%) corn oil), and 2.3 (15.0% corn oil). Papilloma incidence was also affected by diet, with a 79% incidence for the 15.0% corn oil and an incidence of 93% for the 1.0% corn oil group. analyses of the fatty acid composition of epidermal phospholipids in mice fed the experimental diets reflected the dietary LA levels, in that an accumulation of phospholipid LA, accompanied by an overall decrease in arachidonic acid, occurred with increasing dietary corn oil. In spite of the high membrane levels of LA, no measurable amount of epidermal conjugated dienes of LA could be detected. Epidermal prostaglandin E2 levels in acetone-treated mice were similar for all diet groups (approximately 3 pg/micrograms DNA). However, 6 h after topical application with 4 micrograms of TPA, prostaglandin E2 levels were elevated 5- to 10-fold; an inverse correlation (P less than 0.05) was seen with increasing dietary LA, although the concordance with decreased phospholipid arachidonic acid was not strong.(ABSTRACT TR

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Carcinoma; Corn Oil; Dinoprostone; Female; Linoleic Acid; Linoleic Acids; Mice; Mice, Inbred DBA; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate