Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids.
Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta, and eicosanoids synthesized from n-6 fatty acids. Clinical studies have shown that angiogenesis in solid tumors relates to a poor prognosis and, in premalignant lesions, indicates potential for cancerous transformation. High-fat, n-6 fatty acid-rich diets were associated with a relatively poor prognosis in breast cancer patients; in a nude mouse model the same diet enhanced breast cancer progression, whereas n-3 fatty acids exerted suppressive effects that were associated with impaired angiogenesis. Lipoxygenase and cyclooxygenase products of n-6 fatty acid metabolism are angiogenic in in vitro assays. This activity is blocked by pharmacological inhibitors of eicosanoid biosynthesis, and one, indomethacin, suppressed n-6 fatty acid-stimulated murine mammary carcinoma growth and metastasis and tumor vascularization. Review of the experimental data suggests that selective inhibitors of eicosanoid-synthesizing enzymes and dietary intervention with n-3 fatty acids merit clinical evaluation as adjuvant therapy and chemopreventive agents.
Rose
D P
DP
Division of Nutrition and Endrocrinology, American Health Foundation, Valhalla, NY 10595, USA.
Connolly
J M
JM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016228:Endothelial Growth Factors / Q000502:physiology; D005227:Fatty Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000378:metabolism; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000178:diet therapy / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000178:diet therapy / Q000188:drug therapy / Q000209:etiology*; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D004041:Dietary Fats; D015777:Eicosanoids; D016228:Endothelial Growth Factors; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases