Inflammation occurs at sites of foreign invasion or trauma as a result of the induction of cellular signaling hormones called cytokines, which are responsible for changes in tissue physiology, as well as the recruitment of immune cells to damaged areas. Colorectal cancer, the third most frequent cause of cancer death, is intrinsically linked with the inflammatory process. Previous studies have shown that treatment with NSAIDs have a tumor suppressing effect. Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine often seen functioning as a switch that can lead to either apoptosis or proliferation. Ras-mediated signaling through the TGF-beta pathway leads to proliferation, while the Smad-mediated pathway leads toward apoptosis. TGF-beta signaling has been best defined in mouse models where disruption can initiate or promote the neoplastic process.
Polyunsaturated fatty acids (PUFAs), particularly omega-3 and omega-6 fatty acids have been seen in epidemiological studies to have effects on cancer progression, with eicosapentaenoic acid (EPA), an omega-3 PUFA, decreasing tumor vascularity in vivo as well as decreasing pro-inflammatory cytokines. Previous studies in our lab, with athymic nude mice have found that diets with varying ratios of omega-3: omega-6 fatty acids have effects on tumor growth. Increased concentrations of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), have had a suppressive effect, while increased omega-6 fatty acids have had proliferative effects.
Recent feeding studies with varying fatty acid ratios have shown an inverse relationship between individual fatty acids and TGF-beta signaling. In high omega-3 PUFA diets, there is an increase within the splenocytes, a site of macrophage production in nude mice, in TGF-beta signaling, while the tumor shows a decrease. High omega-6 PUFA diets show the opposite results. Within the signaling pathway, phosphorylated JNK and p38, which are associated with Ras, are increased in omega-6 diets and decreased within omega-3 diets. Results suggest that omega-3 and omega-6 have markedly different effects on TGF-beta production and signaling that may turn the switch from apoptotic to proliferative based on diets with various PUFAs.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA