TY - JOUR
T1 - Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis
AU - Lee, Esak
AU - Fertig, Elana J.
AU - Jin, Kideok
AU - Sukumar, Saraswati
AU - Pandey, Niranjan B.
AU - Popel, Aleksander S.
N1 - Funding Information:
We thank Dr Zaver Bhujwalla for providing us with MDA-MB-231, SUM149 and MCF7 breast cancer cell lines for this study; Dr Luigi Marchionni for advice in bioinformatics-based analyses. We also thank Dr Yama Abassi and ACEA Biosciences for the use of the RTCA system in our adhesion and migration assays. This work was supported by the National Institutes of Health grant R01 CA138264, and grants from the Safeway Foundation for Breast Cancer. E.J.F. acknowledges funding from NCI (CA141053).
PY - 2014/9/2
Y1 - 2014/9/2
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms5715
DO - 10.1038/ncomms5715
M3 - Article
C2 - 25178650
AN - SCOPUS:84907313480
VL - 5
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4715
ER -