Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth

Abstract

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3−/−) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3−/−, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3−/−, compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3−/−. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

“…This difference could be explained by the existence of multiple receptors on cell surfaces for PGE 2 , which could compensate or act instead of the EP2 receptor. In this context, it has been shown that human umbilical vein endothelial cells express both EP2 and EP4 (Dormond et al, 2002), and EP3-null mice show decreased tumor growth and angiogenesis (Amano et al, 2003). Moreover, deletion of EP1 and EP4 inhibits tumor development (Watanabe et al, 1999;Mutoh et al, 2002), clearly suggesting that different EP receptors may mediate specific aspects of tumor angiogenesis.…”

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

“…12,13 However, little is known about the direct contribution of COX-2 to lymphedema-associated lymphangiogenesis, although positive correlations between COX-2 expression in tumor tissues and lymphangiogenesis and lymph node metastasis have been reported for several human cancers, [28][29][30] as well as the effect of COX-2 inhibition on lymphangiogenesis in a tumor implantation model. 14 In a study utilizing a nonselective COX inhibitor in a mouse tail lymphedema model, ketoprofen treatment normalized the histopathology with increased TNF-a expression and VEGF-C expression.…”

“…[10][11][12][13] In both inflammatory and tumor models, an inducible cyclooxygenase-2 (COX-2)-derived PGE 2 exerted proangiogenic activity via EP3 signaling, with the concomitant induction of VEGF-A. This effect was especially prominent in bone marrow (BM)-derived cells, which are a major component of tumor stromal tissues.…”

Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway

“…To this end, we used two selective EP 3 R antagonists L-798,106 [19] and ONO-AE 3 -240 [20]. As shown in Figure 4C and D, both EP 3 R antagonists (L-798,106 at 10 μM and ONO-AE 3 -240 at 10 nM) abolished the imetitinduced attenuation of NE exocytosis in cardiac synaptosomes.…”