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Y. Kumagai



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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-002 - Dendritic Cells Promoted the SDF-1-expressing Premetastatic Niche Formation in Mediastinal Lymph Node Metastasis for Lung Cancer via COX-2-derived PGE<sub>2</sub>-EP3 Signaling. (ID 1400)

      09:30 - 09:30  |  Author(s): Y. Kumagai

      • Abstract

      Background
      Lung cancer is the most widespread cause of cancer death in the world. COX-2 derived prostaglandin E~2~ (PGE~2~) is well known to induce tumor growth and metastasis, and thus is associated with a poor prognosis. Lymph node metastasis is also one of the major determinant of the prognosis and is facilitated by lymphangiogenesis, however the precise of the mechanisms is not well understood. In the presenr atudy, we investigated the role of COX-2-derived PGE~2~ on formation of premetastatic niche facilitate the lymph node metastasis in Lung Cancer. Lung cancer is the most widespread cause of cancer death in the world. COX-2 derived prostaglandin E~2~ (PGE~2~) is well known to induce tumor growth and metastasis, and thus is associated with a poor prognosis. Lymph node metastasis is also one of the major determinant of the prognosis and is facilitated by lymphangiogenesis, however the precise of the mechanisms is not well understood. In the presenr atudy, we investigated the role of COX-2-derived PGE~2~ on formation of premetastatic niche facilitate the lymph node metastasis in Lung Cancer.

      Methods
      Male C57BL/6 (6-8 weeks-old, Wild type; WT) and EP3 knockout mice (EP3[-/-]), one of PGE~2~ receptor subtype, were used. Orthotopic intrapulmonary implantation model was made by injecting Lewis Lung Carcinoma (LLC 5.0X10[6] cells/ml) cells into the lung. We estimated the expressions of lymphangiogenic factors, SDF-1/CXCR4, subtypes of EP receptors by immunehistochemical staining, ELISA and real time PCR. The accumulation of immature dendritic cells (iDCs) and regulatory T cells (Tregs) were estimated by immunofluolecent analysis. Furthermore, we estimated the role of iDC on lymph node metastasis by injecting iDCs.

      Results
      The expression of COX-2 and SDF-1, and accumulation of iDCs and Tregs were increased before LLC cell accumulated in lymph node. Compared to vehicle mice, mediastinal lymph node metastasis formations were suppressed with a COX-2 inhibitor (celecoxib, 100mg/kg/day, p.o., P<0.05). Compared to other PGE~2~ subtype receptors, the expression of EP3 receptor was significantly suppressed in celecoxib treated mice (P<0.05). The expression of lymphangiogenesis markers and lymph node metastasis were suppressed in EP3[-/-]. The expression of SDF-1 and accumulations of CD11c[+]DCs and FOXP3[+]Tregs in lymph nodes were significantly suppressed in EP3[-/-] (P<0.05). In vitro study, under PGE~2~ stimulation, the SDF-1 conentration and expression of EP3 in culutured iDCs were significanltly enhanced compared to control. Furthrmore, WT transplanted with EP3[-/-]BM were significantly suppressed mediastinal lymph node metastasis formation compared to WT transplanted with WT mice.

      Conclusion
      These results suggested that premetastatic niche formation in mediastinal lymph node was induced by bone marrow derived immatured dendritic cells via PGE~2~-EP3 signaling by induction of SDF-1-expression. Thus, COX-2 inhibitors, CXCR4 antagonists and/or EP3 antagonists may become one of the options to suppress the lymph node metastasis.