The role of dietary lipid concentration, sources of fat, and specific fatty acid patterns on the incidence and progression of many cancers has been the source of much specula tion and investigation (6,7,21). The human and laboratory evidence is most convincing for a stimulatory effect of dietary lipid concentration, particularly a diet rich in saturated fats, on cancers of the colon and rectum (6,7,21). Less certain, but supported by many studies, are the positive relationships between diets rich in fat and cancers of the prostate, breast, lung, ovary, and endometrium (6,7,21). The possibility that diets rich in omega-3 fatty acids from marine sources have inhibitor properties for cancers has been postulated, and is currently an area of active investigation (6,7,21,109-114).
Dietary lipid intake is primarily in the form of triacylglycerols (triglycerides), with one molecule of glycerol bound to three fatty acids. Dietary fatty acids vary in chain length (typically even numbered, 4-22 carbon atoms in length) and the degree of saturation, which is relevant to biological functions in vivo. Most fatty acids are in a cis configuration in nature, but current food industry techniques, involving the hydrogenation of polyunsaturated vegetable oils for the preparation of variably saturated fats, results in a significant intake of trans fatty acids. Hydrogenated fats are used in cooking and table fats, and as an ingredient in many manufactured foods. The effects of trans fatty acids on metabolism and disease processes remains very controversial. The only specific dietary requirement for lipids in the diet is for essential fatty acids, linoleic acid (18:2) and a-linolenic acid (18:3), which cannot be synthesized by humans.
A linkage between dietary fat and tumor angiogenesis has not been firmly established. However, circumstantial evidence, based on the role of prostaglandins and leukotrienes in modulating endothelial and vascular smooth muscle function, blood vessel dilation/ constriction, and blood clotting, suggests several pathways whereby dietary lipids may influence tumor angiogenesis and related phenomena. Linoleic, arachidonic, eicosapen-tanoic, and related fatty acids are the precursors to a prostaglandin network, in which substrate availability, as well as enzymatic activity, critically regulate the synthesis of specific metabolic products. One example of how dietary lipids can modulate tumor growth and prostaglandin metabolism is derived from the breast cancer literature. Several studies have shown increased breast tumorigenesis with diets higher in total fat concentration (11,43,115). Other reports have documented that the growth of breast cancer cells in culture or in vivo can be modulated by fatty acid patterns (113,114,116-118). Cycloxygenase and lipoxygenase are the two critical enzymes responsible for producing the precursors of eicosanoids. The use of pharmacologic inhibitors of these pathways has clearly demonstrated a role of eicosanoids in breast cancer. Indomethacin treatment, an inhibitor of these two enzymes, suppressed growth and metastasis of mammary cancer, which was stimulated by a high-fat, high linoleic acid rich diet (119). Furthermore, the effect of indomethacin was correlated with lower PGE2 concentrations, one of the principal cyclooxygenase products, in tumors.
The role of endogenous prostaglandins in angiogenesis has been demonstrated by several studies. The inhibitory effect on neovascularization of tumors by several pros-taglandin synthesis inhibitors, including indomethacin, diclofenac, and aspirin, were demonstrated by microangiography studies (120). A recent study examined the ability of a topical application of diclofenac to inhibit prostaglandin metabolism, angiogenesis, and tumorigenesis in a colon carcinoma model (121). Daily treatment with topical diclofenac resulted in a significant inhibition of basal cell skin tumor growth, or subcutaneous colon tumor growth accompanied by a retardation of vascularization development. There was an 80% inhibition of tumor PGE2 synthesis following treatment in the same experiment.
The inhibition of tumor growth, and antimetastatic effects of marine fish oils rich in long-chain omega-3 fatty acids, have been observed in several rodent studies (111,113,122-131). An antiangiogenic effect of omega-3 fatty acids, perhaps via alterations in the synthesis and metabolism of prostaglandins or leukotrienes, is one of several mechanistic hypotheses. McCarty (132) hypothesized that ingestion of omega-3 rich fish oils may impede angiogenesis, and reduce tumor invasiveness by downregulating hormonal activation of protein kinase C (PKC) and by modulating eicosanoid metabolism. Rabbit diets supplemented with sardine oil resulted in a significant 25% inhibition of neovascularization in the corneal alkali-burn injury model (133). Other studies show reduced vascularization and inflammation in immunogenic keratitis of the rabbit cornea by the topical application of eicosapentaenoic acid in eyedrops (134). Further in vitro studies with endothelial cells showed that eicosapentaenoic acid, but not arachidonic or docosahexaenoic acid, was able to inhibit tube formation by endothelial cells in collagen gels, without effects on PGE2 or PGI2 (135). These studies provide indirect evidence supporting the hypothesis that dietary omega-3 fatty acids may inhibit tumor angiogenesis.
One additional mechanism by which dietary fatty acid profiles may modulate angio-genesis is via modulation of cellular signal transduction pathways. Activation of cellular PKC by proangiogenic growth factors and hormone receptors appears to contribute to the synthesis and secretion of collagenase and other lytic enzymes produced by endothelial cells, to enable them to migrate through basement membrane and matrix during angio-genesis (136-140). Omega-3 fatty acid supplementation of endothelial cells in vitro can inhibit activation of PKC (132). In many studies, activation of PKC occurs in conjunction with stimulation of phospholipase C-ß, which is downregulated by EPA (141-146). Additional studies of dietary fatty acid profiles and intracellular signal transduction pathways involved in endothelial proliferation and function are clearly warranted.
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