Activating The Prostaglandin I-2-Ip Signaling Suppresses Metastasis In Lung Cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: The mechanism by which bone marrow (BM)-derived cells might contribute to tumor metastasis and angiogenesis is controversial. We have reported that bone marrow derived angiogenic progenitor cells (Lin- cKit+ Flk-1+ cells) express prostaglandin I2 (PGI2) specific receptor; IP, and the PGI2-IP system is necessary for vascular remodeling and angiogenesis. Additionally, we have reported that the specific knockdown of IP in bone marrow derived cells (BMDCs) increases tumor metastasis in mouse models. Objectives: The purpose of this study was to test the hypothesis that activating the PGI2-IP signaling suppresses tumor metastasis. Materials & Methods: We employed both a mouse lung metastatic model and a mouse bone marrow transplanted model. Mouse-derived Lewis lung carcinoma (LLC) cells labeled with DsRed were used for a mouse lung metastatic model to distinguish cancer cells from BMDCs. The LLCs were injected into the tail vein of mice (c57BL/6J), which bone marrow cells were transplanted from GFP-labeled mice. Beraprost sodium (BPS; IP receptor agonist) or PBS control was continuously administered for 3 weeks by subcutaneous osmotic pumps. Tumor metastasis to lung was assessed by using hematoxylin-eosin staining. The a-SMA as a pericyte marker and the CD31 as an endothelial cell marker were studied by immunofluorescence to evaluate angiogenesis in metastatic lung tumors. Results: The size and number of tumor metastasis were significantly decreased in BPS group compared with in PBS control group assessed by the mice lung metastasis model. Immunofluorescence analysis revealed that the pericytes derived from bone marrow were scattered within tumors in PBS control group, while those were observed along with tumor micro vessels by supporting the endothelial cells within tumors in BPS group. Conclusions: The present study demonstrated that activating the PGI2-IP signaling suppresses metastasis in lung cancer. These results also suggested that the maturation of tumor angiogenesis by pericytes may decrease tumor metastasis. Finally, we propose that PGI2-IP system would be a novel therapeutic target in lung metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4379. doi:1538-7445.AM2012-4379