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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number4715
JournalNature Communications
Volume5
DOIs
StatePublished - Sep 2 2014

Fingerprint

Endothelial cells
metastasis
breast
tumors
Endothelial Cells
cancer
Cells
Breast Neoplasms
Neoplasm Metastasis
Tumors
vessels
Lymphatic Vessels
organs
Neoplasms
angiogenesis
phosphorylation
lymphatic system
Drug Repositioning
Triple Negative Breast Neoplasms
Lymphatic Metastasis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

@article{0d29b0b1d4fe421fb6aa98a5746b87e4,
title = "Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis",
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.",
author = "Esak Lee and Elana Fertig and Kideok Jin and Saraswati Sukumar and Niranjan Pandey and Popel, {Aleksander S}",
year = "2014",
month = "9",
day = "2",
doi = "10.1038/ncomms5715",
language = "English (US)",
volume = "5",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis

AU - Lee, Esak

AU - Fertig, Elana

AU - Jin, Kideok

AU - Sukumar, Saraswati

AU - Pandey, Niranjan

AU - Popel, Aleksander S

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.

UR - http://www.scopus.com/inward/record.url?scp=84907313480&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907313480&partnerID=8YFLogxK

U2 - 10.1038/ncomms5715

DO - 10.1038/ncomms5715

M3 - Article

VL - 5

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4715

ER -