Regulation of Tumor Angiogenesis by Dietary Fatty Acids and Eicosanoids David P. Rose and Jeanne M. Connolly [Nutrition and Cancer 37(2):119-127, 2000. © 2000 Lawrence Erlbaum Associates, Inc.] Abstract 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- , 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. Introduction Angiogenesis, the formation of new blood vessel networks to permit sustained tumor growth, is one of the most rapidly growing fields in basic and applied cancer research, and there has been considerable progress in our understanding of the regulation of angiogenesis by protein growth factors and an emerging delineation of the corresponding signal transduction pathways. However, less appreciated are the accumulating experimental data that indicate the significance of dietary factors in the angiogenesis-dependent growth of tumors and their capacity for local invasion and spread to distant metastatic sites. In this review, we discuss the influence of dietary fatty acids and the eicosanoids derived from the metabolism of polyunsaturated n-6 fatty acids on the process of angio-genesis. These bioactive lipid factors are involved in all the steps in angiogenesis: degradation of the vascular basement membrane and interstitial matrix by proteolytic enzymes such as the type IV collagenases and urokinase-type plasminogen activator (uPA), endothelial cell proliferation and migration, and formation of capillary loops and three-dimensional tubular networks. Also, with particular emphasis on breast cancer, we propose that manipulation of the absolute levels and relative proportion of n-6 and n-3 fatty acids consumed in the diet and the use of selective pharmacological inhibitors of eicosanoid biosynthesis offer novel approaches to antiangiogenesis and, hence, to cancer prevention and treatment. Eicosanoid Synthesis Inhibitors as Antiangiogenesis Agents The development and clinical evaluation of pharmacological and natural antiangiogenic agents is one of the most active areas of cancer research [104-106]. Suramin, one of the earliest but more toxic agents to enter clinical trial, has been shown to exert multiple antiangiogenic effects, including inhibition of vascular endothelial cell uPA expression and bFGF binding capacity and suppression of endothelial cell proliferation and migration [107]. Flavonoids, which occur in a variety of plants and are present at biologically relevant concentrations in some human diets, have anti-angiogenic properties: they block angiogenesis in in vitro assays, suppressing bFGF/VEGF-induced invasion of microvascular endothelial cells by mechanisms that include the inhibition of PKC [108]. We previously remarked on the inhibition of angiogenesis in vitro by COX inhibitors [61,65] and of bFGF-stimulated capillary endothelial cell proliferation by a selective inhibitor of 12-HETE biosynthesis [94]. In similar experiments, Ito and colleagues [109] cocultured human omental microvascular endothelial cells and a human esophageal cancer cell line to demonstrate the antiangiogenic properties of two inhibitors of COX and LOX activity. These novel compounds, a natural lignan and a synthetic derivative, blocked the cancer cell-stimulated endothelial tube formation and the subsequent formation of a vascular network. There is little published work on the antiangiogenic effects of inhibitors of eicosanoid synthesis in animal tumor models. One exception is the report by Lala and co-workers [110]. As part of an investigation into the chemopreventive and chemotherapeutic effects of indomethacin in a spontaneous mouse mammary carcinoma model, they described reduced vascularization in hematoxylin-and-eosin-stained sections of the primary tumors that did develop in the indomethacin-treated animals. Although quantitative analysis of microvessel density by immunohistochemical staining was not performed, this apparent suppression of angiogenesis was associated with twofold reductions in the incidence of lung metastases and in the regression of initially emerging primary tumors. Certainly, the present review indicates that suppressed neovascularization is likely to be a major component in the well-described inhibitory activities of nonsteroidal anti-inflammatory drugs, including indomethacin, on carcinogenesis and tumor progression. When n-3 fatty acid-enriched diets are fed to nude mice bearing human breast cancer xenografts, the uptake of DHA and/or eicosapentaenoic acid into the tumor cell membranes results in the displacement of arachidonate from the constituent phospholipids. The loss of potentially available substrate, together with reduced conversion of LA to arachidonic acid, and n-3 fatty acid-mediated inhibition of COX and LOX, produces dramatic reductions in tumor eicosanoid production, including proangiogenic PGE2 and 12-HETE [47,49]. Furthermore, in addition to this reduction in enzyme substrate, feeding an n-3 fatty acid-containing diet produced a loss of COX-2 mRNA expression in rat mammary glands [111] and a significant reduction of COX-2 and COX-1 immunoreactive protein in N-nitrosomethylurea-induced rat mammary tumors [112]. Data such as these suggested that antiangiogenic effects contributed to the suppression of human breast cancer cell growth and metastasis in the nude mouse model [48,113]. The antiangiogenic activity of DHA has now been demonstrated; partial suppression of the growth of the MDA-MB-231 human breast cancer cell line as solid tumors in nude mice fed the n-3 fatty acid was associated with reduced microvessel formation within the tumor mass, an inhibition of cell proliferation, and increased apoptosis [49]. Where are the human studies? 115 articles call for the NEXT STEP Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.