Potential Angiogenic Role of Platelet-Activating Factor in Human Breast Cancer (original) (raw)

1998, The American Journal of Pathology

This study investigated the presence of platelet-activating factor (PAF) in the lipid extracts of 18 primary breast carcinomas and 20 control breast tissues. The amount of PAF detected in breast carcinomas was significantly higher than in controls. The mass spectrometric analysis of PAF-bioactive lipid extract from breast carcinomas showed the presence of several molecular species of PAF, including C16-alkylPAF, C18-lysophosphatidylcholine (LPC), C16-LPC, lyso-PAF, and C16-acylPAF. The amount of bioactive PAF extracted from breast specimens significantly correlated with tumor vascularization revealed by the number of CD34and CD31-positive cells. As C16-alkylPAF was previously shown to induce angiogenesis in vivo, we evaluated whether the thin layer chromatography-purified lipid extracts of breast specimens elicited neoangiogenesis in a murine model of subcutaneous Matrigel injection. The lipid extracts from specimens of breast carcinoma containing high levels of PAF bioactivity, but not from breast carcinomas containing low levels of PAF bioactivity or from normal breast tissue, induced a significant angiogenic response. This angiogenic response was significantly inhibited by the PAF receptor antagonist WEB 2170. T47D and MCF7 breast cancer cell lines, but not an immortalized nontumor breast cell line (MCF10), released PAF in the culture medium. A significant in vivo neoangiogenic response, inhibited by WEB 2170, was elicited by T47D and MCF7 but not by MCF10 culture medium. These results indicate that an increased concentration of PAF is present in tumors with high microvessel density and that PAF may account for the neoangiogenic activity induced in mice by the lipid extracts obtained from breast cancer. A contribution of PAF in the neovascularization of human breast cancer is suggested. Considerable experimental evidence indicates that formation of new blood vessels is required for tumor growth. 1,2 Moreover, new vessels penetrating into the tumor are frequent sites for entry of tumor cells into the circulation and for formation of metastasis. 2-4 The neoangiogenesis may also be required for the expansion of the metastatic colony. 5-9 It is controversial whether the neoangiogenesis of the primary breast cancer is an independent prognostic marker or not. 10 -17 However, several studies have suggested that the growth and the metastatic dissemination of human breast cancer correlates with the process of angiogenesis. 9,18 -20 Soluble mediators produced by tumor and inflammatory cells have been involved in neoangiogenesis. 4,21 These include polypeptide mediators, such as cytokines and growth factors, nitric oxide, and lipid mediators. In human breast cancer, many angiogenic factors have been related to estrogen regulation of growth and to tumor vascularization. Recent studies link the platelet-activating factor (PAF), a phospholipid mediator of inflammation, 37 to the biological activities of certain polypeptide mediators. 38 It has been found that the angiogenesis induced by tumor necrosis factor (TNF) and hepatocyte growth factor (HGF) is partially due to biosynthesis of PAF. 39,40 PAF, in turn, directly stimulates in vitro migration of endothelial cells and promotes in vivo angiogenesis. 41,42 PAF, which is produced by a broad range of cells, including neutrophils, macrophages, and endothelial cells (reviewed in Refs. 37 and 43), acts through a specific receptor belonging to the family of seven-domain membrane-spanning receptors. 44 It has been reported that PAF triggers diverse and potent biological properties relevant for the development of inflammatory reaction, embryogenesis, and cell differentiation. The presence of PAF was detected in human breast carcinomas but not in nontumor breast tissue. Recently, the production of PAF has been correlated with the formation of pulmonary metastasis in a murine model of melanoma. 46 In addition, PAF was shown to mediate the metastasispromoting activities of TNF-␣ and interleukin (IL)-1␣. Preliminary studies indicate an involvement of PAF in inflammatory neoangiogenesis occurring in humans. 47 In