Author of

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  MO04 - Lung Cancer Biology I (ID 86)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:G. Sozzi, D.C. Lam
  • Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 103, Level 1

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    MO04.11 - The tumor microenvironment expression of the Inhibitor of Differentiation-1 (Id1) is determinant of the development of liver metastasis from lung cancer through gene regulation of tumor cells (ID 2429)

    17:15 - 17:20  |  Author(s): J.M. López-Picazo
    • Abstract
    • Presentation
    • Slides

    Background
    Liver metastases appear in about 30% of non-small cell lung cancer (NSCLC) patients during the disease course with a dramatic impact on clinical outcome and quality of life. TME gene expression might be crucial for allowing tumor cells to migrate and spread to the liver. However, no candidate genes have ever been proposed as responsible for this process. Id1, a member of the gene signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.

    Methods
    For the first time, a mouse model of LM from lung cancer was developed. Two cohorts of mice were compared; C57BL/6 females vs. Id1-knockout (KO) females (gently provided by Dr. Benezra, MSKCC, New York). Lewis lung carcinoma cells (500,000) were selected for intrasplenic injection. Five minutes after tumor cells injection all mice were splenectomized to avoid bulky flank tumor formation. Mice were closely followed after tumor cells inoculation. Weekly FDG-micro-positron emission tomography (PET) scans were performed to study liver metastasis formation in both groups of mice. Animals were sacrificed at the time of LM development. Liver metastatic lesions were obtained for RNA extraction (Qiagen kit). A microarray gene expression analysis (Affymetrix) with the support of Ingenuity Pathways Analysis (IPA) was performed to evaluate the potential impact of Id1 genotype on the regulation of genes mediating proliferation, invasion, migration, angiogenesis and metastasis in LM.

    Results
    The first week after tumor cells intrasplenic injection, FDG-PET scans showed no liver metabolic uptake in any of the mice. By week 2 however, 70% of C57BL/6 mice and 10% of Id1-KO mice showed clear LM by FDG-PET (p=0.02). Three weeks after intrasplenic tumor cells injection, 100% of C57BL/6 animals showed LM compared to 30% of Id1-KO mice (p=0.03). In addition, 50% of Id1-KO mice remained LM-free 4 weeks after tumor cells injection. No other metastatic sites were indentified at the time of necropsy. In the mircroarray gene expression analysis, only a set of 50 out of nearly 900 genes appeared upregulated in the LM of Id1-KO mice compared to C57BL/6 animals whereas the rest of the genes were downregulated. Interestingly, amphiregulin, caveolin-1, aurora kinase B, MMP3, Hsp90aa1, Cdk1, Hif1a, Cyclin D2 were among the significantly downregulated genes in the Id1-KO LM.

    Conclusion
    A novel mouse model for liver metastasis from lung cancer has been developed allowing the study of this complex and unexplored process. Id1 gene expression seems to be a key mediator of the development of liver metastasis from lung cancer in this in vivo model. The absence of Id1 expression in the tumor microenvironment of Id1-KO mice was sufficient to significantly delay and impair the metastatic process of lung cancer tumor cells to the liver. Id1 might be able to modulate LM through a direct downregulation of genes involved in proliferation, invasion, migration, angiogenesis and metastasis. This study has been partially funded by "UTE project CIMA" and an ISCIII-FIS grant 2011.

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