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

Esak Lee, Elana J. Fertig, Kideok Jin, Saraswati Sukumar, Niranjan B. Pandey and Aleksander S. Popel ()
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Esak Lee: Johns Hopkins University School of Medicine
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

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5715

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