Prostacyclin receptor in tumor endothelial cells promotes angiogenesis in an autocrine manner

Abstract

Molecules highly expressed in tumor endothelial cells (TEC) are important for specific targeting of these cells. Previously, using DNA microarray analysis, we found that the prostacyclin receptor (IP receptor) gene was upregulated in TEC compared with normal endothelial cells (NEC). Although prostacyclin is implicated in reendothelialization and angiogenesis, its role remains largely unknown in TEC. Moreover, the effect of the IP receptor on TEC has not been reported. In the present study we investigated the function of the IP receptor in TEC. The TEC were isolated from two types of human tumor xenografts in nude mice, while NEC were isolated from normal counterparts. Prostacyclin secretion levels in TEC were significantly higher than those in NEC, as shown using ELISA. Real-time RT-PCR showed that the IP receptor was upregulated in TEC compared with NEC. Furthermore, migration and tube formation of TEC were suppressed by the IP receptor antagonist RO1138452. Immunohistostaining showed that the IP receptor was specifically expressed in blood vessels of renal cell carcinoma specimens, but not in glomerular vessels of normal renal tissue. These findings suggest that the IP receptor is a TECspecific marker and might be a useful therapeutic target. (Cancer Sci 2012; 103: 1038-1044 A ngiogenesis is essential for tumor growth and metastasis and is an important component of cancer progression. Its inhibition is a valuable new approach to cancer therapy.(1-4) Tumor blood vessels deliver oxygen, nutrients and growth factors to cancer cells and permit their dissemination into the systemic circulation, resulting in metastasis.(5,6) Increased tumor vascularity is associated with poor clinical outcome, and the extent of angiogenesis correlates inversely with patient survival.(6) The inhibition of angiogenesis therefore offers an attractive approach to cancer therapy.The pharmacological targeting of vascular endothelial cells suppresses tumor angiogenesis and growth, and the efficacy of anti-angiogenic therapy has been validated in the clinic. Although a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) prolonged survival in patients with certain types of cancer, some types of tumors appear to be less responsive. The results have been more modest than predicted by most preclinical examinations and improvements in progression-free survival are frequently not accompanied by improvements in overall survival. Furthermore, some side-effects have been reported since VEGF is essential for the survival of normal endothelial cells (NEC).(7-11) A target that is more specific for tumor endothelial cells (TEC) is needed to improve the outcome of antiangiogenic therapy.We previously reported that TEC differ from NEC in gene profile (12,13) and behavior, including enhanced cell survival (14,15) and motility. (16)(17)(18) Using DNA microarray analysis, we previously identified several molecules that were preferentially highly expressed in mouse TEC derived from three different types of human tumor xenografts. ...

Pro-migratory actions of the prostacyclin receptor in human breast cancer cells that over-express cyclooxygenase-2

“…There have been conflicting reports regarding the role of the IP receptor in the motility of tumor-and non-tumor-derived cells. The IP receptor was pro-angiogenic and pro-migratory in endothelial cells [18,23,24]. In contrast, IP receptor activation prevented migration in smooth muscle cells by a cAMP-dependent mechanism [21,22].…”

“…Prostacyclin reportedly activates migration in endothelial cells [18], but was anti-migratory in melanoma and certain rodent tumor cells [19,20] and in some non-tumor cell types, including myocytes, where it activates cAMP-dependent pathways [21,22]. Prostacyclin has also been shown to activate angiogenesis, which promotes the development of vascular structures that facilitate tumorigenesis [18,23,24]. Whether prostacyclin also activates metastatic behavior in breast cancer-derived cells has not been evaluated directly.…”

Prostanoids regulate angiogenesis acting primarily on IP and EP4 receptors

“…The IP receptor activates both cAMP synthesis (through Gs subunit activation) and the PKC pathway in a Gq-dependent manner (Bos et al, 2004). EP4 has been found to be most important in the regulation of angiogenesis by PGE 2 (Rao et al, 2007;Yanni et al, 2009), whereas proangiogenic processes in endothelial cells may be suppressed by IP antagonism (Osawa et al, 2012).…”

Inhibition of Multidrug Transporter in Tumor Endothelial Cells Enhances Antiangiogenic Effects of Low-Dose Metronomic Paclitaxel

“…After subculture for approximately 2 weeks, isolated ECs were further purified using FITC-BS1-B4-lectin. 25 All the purified ECs were cultured in EGM-2MV and were used at passages 15 to 25.…”