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J. Varano



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.06 - The role of fibroblast growth factor-9 in the regulation of the tumour-specific immune response in malignant mesothelioma (ID 3237)

      10:30 - 12:00  |  Author(s): J. Varano

      • Abstract
      • Presentation
      • Slides

      Background
      Identifying key molecules in the pathobiology of malignant mesothelioma is needed to develop new therapies and biomarkers. Fibroblast growth factor-9 (FGF-9) is an exciting and novel target uncovered from our global gene profiling of human MPM samples. Recently FGF-9 has been implicated in cancer development and neoplastic transformation of embryonic fibroblasts. We have verified over-expression of FGF-9 in MPM over other cancers and benign pleuritis in five separate cohorts of human pleural tissues and effusions. Our preliminary in vitro work demonstrated that FGF-9 induces mesothelioma cell proliferation and matrix invasion. We therefore hypothesised that antagonising FGF-9 may reduce tumour aggressiveness, growth and induce tumour regression in vivo.

      Methods
      To study the ‘necessity’ of FGF-9 in MPM development in vivo we transfected the mouse MM cell line, AB1, with shRNA directed against murine FGF-9 (or control vector expressing a scrambled sequence). For the heterotopic model murine AB1-FGF-9 knock-down cells (or controls) were injected (5x10[5 ]cells) subcutaneously into the flank of Balb/c mice. Tumour dimensions were measured thrice weekly and animals sacrificed when tumours reached 100mm[2] and tumour tissues harvested. FGF-9 expression in tumour tissue was determined by immunohistochemistry. For orthotopic experiments, Balb/c mice received a single intraperitoneal injection of 5x10[5 ]AB1-FGF-9 knock-down cells (or controls). At day 13, animals were sacrificed and the number of peritoneal tumour nodules enumerated by blinded investigators. To determine whether the immune system plays a role in the regulation of AB1 MM tumour growth, 5x10[5 ]AB1-FGF-9 knock-down cells (or controls) were injected subcutaneously into nude mice. To elucidate the immune cells involved in AB1 MM tumour growth regulation, T cells were depleted in Balb/c tumour bearing mice using specific antibodies to CD4 and CD8 and tumour growth monitored. T cell depletion was confirmed using flow cytometry.

      Results
      Heterotopic tumour growth was significantly retarded in mice inoculated with AB1-FGF-9 knockdown cells compared to the scrambled vector and parent MM cells (p<0.001). A significant reduction in the number, and hence tumour burden, of tumour nodules was also observed for AB1-FGF-9 knockdown tumours in the orthotopic peritoneal model compared to controls (p<0.001). When grown in nude mice, which lack a functional T cell repertoire, AB1-FGF-9 knockdown tumours grew at a similar rate to that of the parent and vector controls which was suggestive of a role of the immune response in the regulation of MM tumours lacking FGF-9. AB1-FGF-9 knockdown tumours demonstrated significantly greater tumour burden in mice depleted of CD4+ and CD8+ T cells, either alone or in combination, when compared to saline controls which is highly suggestive of a T cell-mediated immune response to these tumours. These results also suggest that FGF-9 inhibits the tumour-specific immune response in MM.

      Conclusion
      In combination with our previous in vitro data which clearly demonstrated the proliferative and invasive properties of FGF-9, we suggest that FGF-9 has an important role in the pathobiological characteristics of MM in vivo and represents a novel therapeutic target.

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