{'fraction_non_alphanumeric': 0.02943939868462261, 'fraction_numerical': 0.013153773880363295, 'mean_word_length': 5.049242424242424, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
A new link in ovarian cancer angiogenesis: lysophosphatidic acid and vascular endothelial growth factor expression.

The switch to the angiogenic phenotype (1) is under genetic and epigenetic regulation. An example of genetic regulation of the angiogenic switch is expression of the HER-2/neu oncogene, which increases expression of vascular endothelial growth factor (VEGF), a positive regulator of angiogenesis in human breast cancer (2). Another example is expression of the ras oncogene, which increases expression of VEGF and decreases expression of thrombospondin-1, a negative regulator of angiogenesis. At least 13 other oncogenes are known to encode proteins that drive tumor angiogenesis (2). By contrast, certain tumor suppressor genes override the angiogenic switch; e.g., p53 normally maintains thrombospondin-1 production (3). Epigenetic regulation of the angiogenic switch is illustrated by increased VEGF expression in tumor cells by hypoxic induction of hypoxia-inducible factor-1 (4) or by triggering angiogenesis by matrix metalloproteinase-9 during carcinogenesis (5). Overexpression of VEGF by ovarian cancer cells is a major mediator of angiogenesis in this tumor type. In the ascites fluid of human OVCAR-5 ovarian cancer in mice, we have found VEGF levels of more than 6000 pg/mL and, in the same mice, serum levels in the range of only 30 pg/mL (Wen W, Panigrahy D, Butterfield C: personal communication, unpublished data). When OVCAR-5 cells were grown in vitro, VEGF levels in the conditioned medium reached greater than 1400 pg/mL compared with less than 30 pg/mL for control medium without the tumor cells. In a patient with ovarian cancer, VEGF levels in the ascites fluid were greater than 13 000 pg/mL. In a report in this issue of the Journal, Hu et al. (6), working with Napoleone Ferrara, a leading figure in angiogenesis research, have unraveled a novel pathway for VEGF expression in ovarian cancer. They show that lysophosphatidic acid (LPA) in ovarian cancer ascites fluid binds to a receptor for the endothelial differentiation gene (Edg4), which is expressed in ovarian cancer cells but not in normal ovarian epithelial cells. The result of ligand binding is increased VEGF expression by the cancer cells. Activation of the Edg4 receptor increased expression of the VEGF promoter by a mechanism that is mediated through c-Jun and c-Fos and differs qualitatively from hypoxia-mediated increased VEGF expression through increases in the half-life of VEGF messenger RNA. As the authors emphasize (6), these results suggest that Edg4 may provide a new target for therapy in ovarian cancer. This report is of great interest because it suggests the possible development of a novel angiogenesis inhibitor that could shut off the angiogenic switch in ovarian cancer or at least control one aspect of this switch. Antiangiogenic therapy could also reduce ascites, as has been demonstrated previously in animals (7,8). Because LPA is mitogenic for ovarian cancer cells, an Edg4 inhibitor could also directly block cancer cell proliferation. There are two general classes of angiogenesis inhibitors, indirect and direct. A drug that would decrease VEGF expression