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Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis

Author

Listed:
  • Esak Lee

    (Johns Hopkins University School of Medicine
    School of Engineering, Johns Hopkins University)

  • Elana J. Fertig

    (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine)

  • Kideok Jin

    (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine)

  • Saraswati Sukumar

    (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine)

  • Niranjan B. Pandey

    (Johns Hopkins University School of Medicine)

  • Aleksander S. Popel

    (Johns Hopkins University School of Medicine
    School of Engineering, Johns Hopkins University
    The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine)

Abstract

Breast cancer metastasis involves lymphatic dissemination in addition to hematogenous spreading. Although stromal lymphatic vessels (LVs) serve as initial metastatic routes, roles of organ-residing LVs are underinvestigated. Here we show that lymphatic endothelial cells (LECs), a component of LVs within pre-metastatic niches, are conditioned by triple-negative breast cancer (TNBC) cells to accelerate metastasis. LECs within the lungs and lymph nodes, conditioned by tumour-secreted factors, express CCL5 that is not expressed either in normal LECs or in cancer cells, and direct tumour dissemination into these tissues. Moreover, tumour-conditioned LECs promote angiogenesis in these organs, allowing tumour extravasation and colonization. Mechanistically, tumour cell-secreted IL6 causes Stat3 phosphorylation in LECs. This pStat3 induces HIF-1α and VEGF, and a pStat3-pc-Jun-pATF-2 ternary complex induces CCL5 expression in LECs. This study demonstrates anti-metastatic activities of multiple repurposed drugs, blocking a self-reinforcing paracrine loop between breast cancer cells and LECs.

Suggested Citation

  • Esak Lee & Elana J. Fertig & Kideok Jin & Saraswati Sukumar & Niranjan B. Pandey & Aleksander S. Popel, 2014. "Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis," Nature Communications, Nature, vol. 5(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5715
    DOI: 10.1038/ncomms5715
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