Abstract 5487: Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and usefulness of TMPRSS4 as a molecular target for synergistic efficacy.

Abstract

Abstract Prostaglandin E2 (PGE2) plays an important role in cancer cell growth, progression, and metastasis and exerts its effects by binding to E-prostanoid receptor (EP). In the previous study, we showed that soluble fragment of EP2 receptor containing the second extracellular region (FuEP2/Ex2) has neutralizing activity to PGE2 and inhibits the growth of prostate and endometrial cancer cells. Here, we established a stable transfectant expressing FuEP2/Ex2 from human ovarian cancer SKOV/ip cells (SKOV/ip-FuEP2/Ex2) and SKOV/ip-FuEP2/Ex2 and vector-control cells were injected into nude mice intraperitoneally. Tumor weight and ascites volume in SKOV/ip-FuEP2/Ex2-injected mice decreased significantly compared to control cell-injected mice. Furthermore, microvessel density and numbers of M2-poralized macrophage in tumor lesion were significantly decreased in SKOV/ip-FuEP2/Ex2-injected mice. By using RNAs from tumor lesion in each group, the cDNA microarray analysis was also conducted. Six of upregulated genes and eight of downregulated genes in SKOV/ip-FuEP2/Ex2-derived tumor were identified. In upregulated genes, MMP-7, TMPRSS4, and CYP1B1, which is involved in cancer progression and metastasis, were included. Treatment with AEBSF, an inhibitor of TMPRSS4, or siRNA for TMPRSS4 further reduced cell growth of SKOV/ip-FuEP2/Ex2 cells in vitro and in vivo. Our results suggest that FuEP2/Ex2 has a suppressive effect in peritoneal metastasis model of ovarian cancer and that MMP-7, TMPRSS4, and CYP1B1 may act as a survival factor under the condition in which EP-mediated signaling are inhibited. Moreover, targeting of TMPRSS4 may enhance the inhibitory effect of FuEP2/Ex2 on ovarian cancer metastasis. Citation Format: Tetsuyuki Takahashi, Hisanori Uehara, Keisuke Izumi. Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and usefulness of TMPRSS4 as a molecular target for synergistic efficacy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2013-5487