Satoshi Endo

Prostaglandin I2 analog suppresses lung metastasis by recruiting pericytes in tumor angiogenesis.

Prostaglandin I2 (PGI2) agonist has been reported to reduce tumor metastasis by modifying tumor angiogenesis; however, the mechanisms of how PGI2 affects the endothelial cells or pericytes in tumor vessel maturation are still unclear. The purpose of this study was to clarify the effects of PGI2 on tumor metastasis in a mouse lung metastasis model using Lewis lung carcinoma (LLC) cells. The mice were treated continuously with beraprost sodium (BPS), a PGI2 analog, for 3 weeks and then examined for lung metastases. The number and size of lung metastases were decreased significantly by BPS treatment. In addition, scanning electron microscopy and immunohistochemistry revealed that BPS increased the number of tumor‑associated pericytes and improved intratumor hypoxia. Collectively, this study suggests that BPS attenuated vascular functional maturation in metastatic tumors.

Primary Mediastinal Amyloidosis Diagnosed by Transbronchial Needle Aspiration

A 61-year-old woman was referred for an evaluation of mediastinal lymphadenopathy (arrowheads indicate mediastinal lymph nodes) (Picture 1). Some of the nodes had partial calcification. Hilar lymphadenopathy and diffuse interstitial changes in the lungs were absent. Positron emission tomography revealed an uptake of F-fluorodeoxyglucose in the mediastinum (Picture 2). A histological analysis using endobronchial ultrasound-guided transbronchial needle aspi-

Histamine H1 antagonist levocetirizine as a potential cause of lung injury

Histamine H1 antagonists rarely cause drug‐induced lung injury (DLI). A woman in her 60s, who had been taking antihistaminic levocetirizine for 2 months, presented with progressive cough and shortness of breath. A chest radiograph showed patchy infiltrations on both lower lung fields. Chest computed tomography findings were consistent with non‐specific interstitial pneumonia. Serum markers associated with interstitial pneumonias were elevated. Room air arterial blood gas analysis revealed hypoxemia. Restrictive ventilatory impairment was noted with reduced diffusing capacity. Transbronchial lung biopsy specimens demonstrated unclassifiable alveolitis. Steroid pulse therapy was introduced for respiratory distress, but the initial response to treatment was poor. A drug lymphocyte stimulation test was positive for levocetirizine. The interstitial pneumonia improved following withdrawal of levocetirizine. Her illness has not recurred under steroid therapy and the discontinuation of levocetirizine. Antihistaminics may have a potential risk of DLI.

A case of cervicogenic headache caused by C5 nerve root derived shwannoma: Case report

Introduction We report a case of cervicogenic headache caused by an intradural extramedullary tumor of the middle cervical spine, which has not previously been reported. Case presentation The patient was a 73-year-old male who visited a physician for a chief complaint of pain from the left lower jaw to the auricle and occipital region. The headache was induced with retroflexion of the neck. On cervical magnetic resonance imaging, an intradural extramedullary tumor was noted on the left side at the C4/5 level. The intradural tumor, which arose from the C5 nerve root, was excised and the pain was resolved. The pathological diagnosis was schwannoma. Conclusion Previously reported cases of spinal cord tumor-induced cervicogenic headache were due to upper cervical spinal tumors. This is the first report that a middle-lower cervical intradural extramedullary tumor caused cervicogenic headache.

Abstract 371: PGI2 analog enhances endothelial-pericyte interactions and suppresses lung metastasis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Endothelial cells (ECs) express IP (prostaglandin I2 (PGI2) specific receptor) and are playing important role in tumor angiogenesis. We have reported that the PGI2-IP system is necessary for vascular remodeling and angiogenesis. Additionally, we have reported that the knockdown of IP increases tumor metastasis in mouse models. Objectives: In this study, we examined whether the activated PGI2-IP signaling could enhance EC-PC interactions and suppress tumor metastasis. Materials & Methods: Mouse-derived Lewis lung carcinoma (LLC) cells were used for a mouse lung metastatic model, and were injected from the tail vein of mice (c57BL/6J). Beraprost sodium (BPS; PGI2 analog) was continuously administered for 3 weeks. Tumor metastasis to lung was assessed by using hematoxylin-eosin staining. The a-SMA and the NG2 as a pericyte marker and the endomucin as an endothelial cell marker were analyzed by immunofluorescence to evaluate angiogenesis in metastatic lung tumors. The structure of the tumor blood vessels was analyzed by scanning electron microscopy (SEM). Results: The size and number of lung metastatic nodules were significantly decreased in BPS group compared with in control group assessed by the mice lung metastatic model. Immunofluorescence analysis revealed that the number of vessel-associated a-SMA+ cells was significantly increased by BPS administration. Scanning electron microscopy revealed that pericytes covering the tumor blood vessels increased in BPS group. Conclusions: The present study demonstrated that BPS suppresses lung metastasis in our model. These results also suggested that the maturation of tumor blood vessels by pericytes may decrease tumor metastasis. Finally, we propose that BPS would be a novel therapeutic target in lung metastasis. Citation Format: Yoshinori Minami, Takaaki Sasaki, Satoshi Endo, Kiyoko Shibukawa, Yoshinobu Ohsaki. PGI2 analog enhances endothelial-pericyte interactions and suppresses lung metastasis. [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 371. doi:10.1158/1538-7445.AM2013-371

Abstract 4379: Activating the prostaglandin I2-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

Abstract 1576: Prostaglandin I2 signaling regulates micro-metastasis in lung cancer

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 didn9t 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