Abstract Background: Bone marrow-derived cells (BMDCs) play an important role in the initiation of neo-angiogenesis, and contribute to the diseases including ischemic diseases, retinopathy, and cancer. We have reported that BMDCs express prostaglandin I2 (PGI2) specific receptor, IP and the PGI2-IP signaling system maintains the function of BMDCs. Additionally, we have reported that the PGI2-IP signaling in BMDCs play an important role for tumor growth, by using mouse bone marrow transplanted models and tumor xenograft mouse models. Objectives: The purpose of this study was to test the hypothesis that PGI2-IP signaling system regulates micro-metastasis in lung cancer. Methods: In vitro study, 5-bromo-2’-deoxy-uridine (BrdU) cell proliferation assay and clonogenic cell assay were used to clarify the effect on lung cancer cell (A549, PC9) proliferation and cellular form in the existence of IP receptor agonist or antagonist. Human cytokine antibody array was performed to detect the expression of angiogenic cytokines and growth factors secreted by the treated cells. In vivo study, we employed both a mouse lung metastasis model and a mouse bone marrow transplantation model. We used GFP-labeled or DsRed-labeled lung cancer cells to distinguish cancer cells from BMDCs. Lung cancer cells were injected into the tail vein of mice (ICR nu/nu), which were transplanted with bone marrow cells from GFP-labeled wild-type or IP knockout mice. Real-time RT-PCR was used to quantify lung metastasis of human cancer cells in nude mice, and the expression levels of housekeeping genes (human and mouse GAPDH) in the lungs were measured. Immunofluorescence assay was performed to evaluate angiogenesis in pulmonary metastatic tumors. Results: In vitro study, PGI2-IP signaling didn't impair proliferation of lung cancer cells and production of angiogenic cytokines secreted by tumors. In the mice lung metastasis model, micro-metastasis in lung cancer was regulated by PGI2-IP signaling system. RT-PCR assay showed that PGI2-IP signaling changed the expression levels of human lung cancer cells in mice lungs. In the immunofluorescence assay, PGI2-IP signaling influenced the expression of pericyte markers around the tumors. Conclusions: The present study demonstrated that PGI2-IP signaling system regulates micro-metastasis in lung cancer. These results suggest that PGI2-IP system may become a novel therapeutic target in lung metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1576. doi:10.1158/1538-7445.AM2011-1576