Author of

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  P2.03 - Biology (ID 162)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30830

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    P2.03-48 - Tumor-Derived Granulocyte Chemotactic Protein 2 Cooperates with Proteases to Drive Lung Adenocarcinoma (ID 1326)

    10:15 - 18:15  |  Author(s): Stefanie Anne Weiß
    • Abstract

    Background
    

    Introduction: Lung adenocarcinoma (LADC) commonly arises in the lungs of smokers that are heavily affected by chronic inflammation. Inflammatory signaling from tumor to host cells is critically involved in the pathogenesis of LADC, but the exact mechanisms by which the lung epithelium interacts with the immune system during carcinogenesis are obscure.

    Objectives: We discovered that murine and human LADC cell lines overexpress the inflammatory and angiogenic CXC chemokine granulocyte chemotactic protein 2 (GCP2, CXCL6) compared with normal epithelial cells. GCP2 is processed by immune proteases: neutrophil elastase (NE, ELANE), proteinase 3 (PR3, PRTN3) and matrix metalloproteinase 9 (MMP9, MMP9). We suppose that GCP2 interacts with these proteases to drive LADC and aimed at investigating its function(s).

    Method
    

    GCP2, MMP9 and PR3 expressions were determined by ELISA and immunohistochemistry. Mouse and human microarray data were analyzed using Affymetrix Transcriptome Analysis Console. GCP2 silencing using dedicated shRNA pools (SantaCruz Biotechnology) and NE/PR3 or MMP9 compound knockout mice were used to study GCP2 interaction with immune proteases in LADC progression.

    Result
    

    Murine and human LADC tumors and cell lines overexpress GCP2, MMP9, NE and PR3 at the mRNA and protein levels. GCP2 is sequestered to tumor cells, whereas proteases are produced by tumor-infiltrating immune cells. LADC-secreted GCP2 is incompletely processed and require MMP9, NE or PR3 for full activation and vasoactive effects. Moreover, GCP2-silenced LADC cells injected in mice show a lack in metastasis formation.

    Conclusion
    

    Our results indicate that tumor-originated GCP2 cooperates with immune proteases to drive LADC, providing a paradigm of how the respiratory epithelium coopts the innate immune system during carcinogenesis.