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Y. Yamada

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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.14 - SuppressionĀ of Lung Cancer Growth by CD26/DPP4 Inhibitor (ID 1546)

      10:45 - 12:15  |  Author(s): Y. Yamada

      • Abstract
      • Presentation
      • Slides

      Lung cancer is the most prominent cause of death among cancers, accounting for 1.38 million deaths worldwide annually. In spite of improved treatment in surgery, chemo- and radiation therapy, the five year survival is poor, being 69% for stage Ia and <5% for stage IV. The cure rates of current therapies are disappointing and did not significantly prolong long term survival. Surfactant protein (SP) in lung determines not only function of the organ, but also inflammatory reaction in an infectious condition. Recently Nishioka et al. showed that stimulated SP production in the orthotopic models of human lung cancer recruits inflammatory, type I macrophages in the tumor which decreased the size of the tumor. Also, Stephan et al. found increased productions of SPs in rat by CD26/DPP4 inhibitor treatment or CD26-/- animal. In our previous work, we found the activity of CD26/DPP4 of lung cancer from patients was four times higher than normal lung tissue from same patients (n=38). Therefore, we tested if pharmacological CD26/DPP4 inhibitor (Vildagliptin) inhibits lung cancer growth in various animal models.

      Mouse lung cancer cell line (Lewis Lung Carcinoma (LLC)) and human lung adenocarcinoma cell line, H460, were used to develop syngeneic (C57BL6: n=8) or xenogeneic (CD1-nude: n=20) tumor models by sc. injection. Tumor growth was represented by wet weight of tumor mass at harvest (4 weeks). BALB/c mouse strain (n=12) was used to induce lung cancer by Urethane (1g/kg) ip. Urethane injected mice were harvested 5 months after ip. Vildagliptin treatment was given in drinking water (0.2 mg/ml: 50mg/kg day) during the experimental course. Tumor nodules were counted macroscopically under surgical microscope. For histological assessment, HE, TUNEL, immunohistochemistry (IHC) of CD31, Ki67, CD3, Nkp46, and F4/80 were performed. The expression of surfactant protein C (SP-C) was detected by western blotting.

      Vildagliptin treatment significantly reduced the size of tumor developed by lung cancer cell line injection (p<0.05 for both). Tumor induced by Urethane ip. in BALB/c mice was less incident by Vildagliptin treatment (40%: 2/5 mice) than control (100%: 7/7) group. The number of tumor nodule per mouse was also significantly reduced by Vildagliptin compared to control (p<0.05). Beside tumor weight, there was no difference in HE, TUNEL stain, and IHCs of CD31, Ki-67, CD3, and Nkp46. However we found significantly increased numbers of macrophages (F4/80) in the tumors induced by lung cancer cell line injection (p<0.05 for both) along with increased expression of SP-C in lung cancer cell lines in vitro.

      Inhibition of CD26/DPP4 by Vildagliptin decreased lung cancer growth in the models of mouse and human lung cancer cell lines and increased infiltrating macrophages within tumors. Furthermore, there was increased expression of SP-C by Vildagliptin treatment found in lung cancer cell lines. This finding suggests that surfactant production in lung cancer is induced and potentially activates macrophages against lung cancer by CD26/DPP4 inhibitor, Vildagliptin.

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