Author of

• 20186

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  P3.07 - Immunology and Immunotherapy (ID 723)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Immunology and Immunotherapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24111

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    P3.07-002 - Blocking of ADAM17 Mitigates Kras-Induced Lung Adenocarcinoma Possibly via Inhibition of IL-6 Trans-Signaling (ID 7942)

    09:30 - 09:30  |  Author(s): S. Rose-John
    • Abstract
    • Slides

    Background:
    Lung adenocarcinoma (LAC) accounts for approximately 40% of all lung cancers, the leading cause of cancer death worldwide. Oncogenic Kras mutations are a common feature of LAC, although the identity of signaling networks which engage Kras to promote LAC remains ill-defined. Moreover, LAC is characterised by dysregulated inflammatory responses, which contribute to tumor promotion and progression. In that regard, we have identified a requirement for interleukin-6 (IL-6) in the molecular pathogenesis of Kras-driven LAC. Specifically, this was dependent on the soluble IL-6 receptor (sIL-6R), which is produced by proteolytic cleavage of the membrane-bound IL-6R by a disintegrin and metalloproteinase 17 (ADAM17), also known as the TNFα-converting enzyme (TACE). Although clinical studies indicate that ADAM17 (mRNA and protein) is upregulated in lung cancer and correlate with poor prognosis, the role of ADAM17 in promoting Kras-driven LAC remains unknown. Here, we sought to investigate the role of ADAM17 in the pathogenesis of Kras-induced LAC.
    
    Method:
    We coupled the Kras[G12D] LAC mouse model with Adam17[ex/ex] mice, which are homozygous for a hypomorphic Adam17 allele resulting in a dramatic reduction in ADAM17 protein expression. Oncogenic Kras[G12D] was activated using intranasal inhalation of Adenovirus Cre recombinase. Mice were culled 6 weeks following inhalation and LAC was evaluated using histopathology (H & E staining). Moreover, immunohistochemical analyses were carried out to assess markers for LAC (TTF-1), proliferation (PCNA) and inflammation (CD45). Serum sIL-6R levels were measured using ELISA. Quantitative PCR was also performed to assess the expression of IL-6 target genes.
    
    Result:
    Following Kras activation, Adam17[ex/ex] mice showed significant reduction in the area of lung parenchyma affected by tumor lesions. This was associated with reduced TTF-1 levels and cellular proliferation. Furthermore, reduced ADAM17 expression mitigates the inflammatory response associated with LAC. Serum levels of sIL-6R were significantly reduced in Adam17[ex/ex] mice, with significant down-regulation in IL-6 target genes.
    
    Conclusion:
    In conclusion, our data suggests that blocking of ADAM17 may represent an attractive therapeutic target for tackling LAC.
    
    

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