Effects of dietary fatty acids on intestinal tumorigenesis in Apc(Min/+) mice

Dietary fat is thought to be an important environmental factor influencing colorectal cancer risk. n-3 polyunsaturated fatty acids (PUFA) have been linked to a lower risk of colorectal cancer and it has been presumed that this effect is due to their ability to interfere with synthesis of 2-series prostaglandins from arachidonic acid (AA, 20:4 n-6). However, the specific mechanism has not been clearly established. Therefore, we hypothesized that select dietary fatty acids would modulate intestinal tumorigenesis through interference with AA metabolism in the ApcMin/+ mouse, a unique model system bearing many similarities to human intestinal cancer. α-linolenic acid (ALA, 18:3 n-3), stearidonic acid (SDA, 18:4 n-3), eicosapentaenoic acid (EPA, 20:5 n-3), and docosahexaenoic acid (DHA, 22:6 n-3) significantly reduced phospholipid AA concentrations and prostaglandin levels compared to controls, but only SDA and EPA significantly reduced overall tumor number and size. Two other PUFA also proposed to be anti-tumorigenic, conjugated linoleic acid (cLA, 18:2 n-6 and n-7) and γ-linolenic acid (GLA, 18:3 n-6), did not significantly alter AA concentrations, prostaglandins, or tumorigenesis. The effects of EPA on phospholipid AA levels, prostaglandins, and tumorigenesis were eliminated when equivalent amounts of AA were provided concomitantly in the diet, indicating that EPA exerts its anti-tumorigenic effect, at least in part, through antagonism of arachidonic acid and/or its metabolism. Selective inhibition of Δ-6 desaturase, the rate-limiting step in de novo AA biosynthesis, likewise resulted in 37% fewer tumors compared to controls and this was normalized when AA was provided concomitantly in the diet indicating that inhibition of de novo AA biosynthesis inhibits tumorigenesis in this model. Finally, the nonsteroidal anti-inflammatory drugs (NSAIDs) piroxicam and sulindac, which are also inhibitors of prostaglandin biosynthesis, are able to regress preexisting intestinal tumors. Bypassing prostaglandin inhibition with concomitant NSAID and PGE ₂ receptor agonist treatment muted the anti-tumorigenic effects of both NSAIDs, indicating that prostaglandin inhibition is responsible, in part, for the anti-tumorigenic effect of NSAIDs. Additionally, treating ApcMin/+ mice with an anti-PGE ₂ antibody, which prevents PGE₂ from binding to its receptors and eliciting cellular responses, also resulted in 33% fewer tumors. This research firmly establishes a role for AA and for AA-derived prostaglandins in promotion of intestinal tumorigenesis.