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

Lee, Esak; Fertig, Elana J.; Jin, Kideok; Sukumar, Saraswati; Pandey, Niranjan B.; Popel, Aleksander S.

doi:10.1038/ncomms5715

Cited by 199Lymphatic System and DiseasesCancer Cells and MetastasisLymphatic Disorders and Treatments

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

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Lee, Esak, Fertig, Elana J., Jin, Kideok, Sukumar, Saraswati, Pandey, Niranjan B., Popel, Aleksander S.·2014·Nature Communications

DOI 10.1038/ncomms5715PMC PMC4351998

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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.

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Breast cancer cells condition the premetastatic niche through tumor-lymphatic vessel cross-talk.
“Another mechanism by which breast cancer cells condition the premetastatic niche is through tumor-lymphatic vessel cross-talk.”
From Hypoxic control of metastasis (2016) · cites this paper as [98]
IL-6-induced VEGF expression in LECs is associated with activation of HIF-1.
“Interestingly, IL-6–induced VEGF expression in LECs is associated with the activation of HIF-1”
From Hypoxic control of metastasis (2016) · cites this paper as [98]
Lymphatic vessels at the distant site support metastatic colonization in breast, melanoma, prostate, gastric, and colon cancer patients.
“Lymphatic vessels at the distant site support metastatic colonization in breast, melanoma, prostate, gastric, and colon cancer patients (98).”
From Hypoxic control of metastasis (2016) · cites this paper as [98]
IL-6 secretion by the tumor activates STAT3 signaling in LECs localized within the lymph node and lung to promote CCL5-mediated recruitment of CCR5-positive breast cancer cells into the lymphatic system and VEGF-mediated lung vascular permeability and lymph node angiogenesis.
“IL-6 secretion by the tumor activates signal transducer and activator of transcription 3 (STAT3) signaling in LECs localized within the lymph node and lung to promote (i) CCL5-mediated recruitment of CCR5-positive breast cancer cells into the lymphatic system and (ii) VEGF-mediated lung vascular permeability and lymph node angiogenesis (98).”
From Hypoxic control of metastasis (2016) · cites this paper as [98]
LECs within premetastatic organs are conditioned by tumor-derived factors to facilitate tumor cell recruitment, extravasation, and colonization.
“LECs within premetastatic organs are conditioned by tumor-derived factors to facilitate tumor cell recruitment, extravasation, and colonization (98).”
From Hypoxic control of metastasis (2016) · cites this paper as [98]

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[54]Lee E Pandey NB Popel AS Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model Clin Exp Metastasis 2013 PMC3947147 23963763

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Abstract B27: Lymphatic endothelium promotes angiogenesis, tumor growth, and metastasis in breast cancer
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Abstract 4084: Crosstalk between TNBC and stromal components via secreted factors enhances cell motility that can be attenuated by a CXCR1 inhibitor
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Authors: Lee, E., Fertig, E. J., Jin, K., Sukumar, S., Pandey, N. B., & Popel, A. S.
Affiliations: Johns Hopkins University (US)
Corresponding author: Popel, Aleksander S.
ORCID: Lee, Esak
Fertig, Elana J.
Jin, Kideok
Sukumar, Saraswati
Pandey, Niranjan B.
Popel, Aleksander S.
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2014-09-02
Volume: 5
Issue: 1
Pages: 4715-4715
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/ncomms5715
PMC: PMC4351998
OpenAlex: W2001868807
Cited by: 197
References: 56
Citations by year: 2026: 10 · 2025: 18 · 2024: 14 · 2023: 21 · 2022: 22 · 2021: 20 · 2020: 26 · 2019: 10 · 2018: 13 · 2017: 12 · 2016: 19 · 2015: 8 · 2014: 3
FWCI: 6.75
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Communications (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (MDA-MB-231)
National Cancer Institute (CA141053, K25CA141053, R01CA138264)
Topics: Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
Keywords: breast cancer metastasis, lymphatic endothelial cells, pre-metastatic niche, triple-negative breast cancer, RANTES, interleukin-6, STAT3 signaling, HIF-1α, vascular endothelial growth factor, angiogenesis, paracrine signaling, drug repurposing, lymphatic dissemination, lung metastasis, lymph node metastasis
MeSH terms: Maraviroc, Interleukin-6 Inhibitors, Aminosalicylic Acids, Animals, Benzenesulfonates, Cell Adhesion, Cell Movement, Cyclohexanes, Female, Humans, Lung, Lymph Nodes, Lymphatic Metastasis, Mice, Nude, Neoplasm Transplantation, Transplantation, Heterologous, Triazoles, Interleukin-6, Gene Expression, Culture Media, Conditioned, Chemokine CCL5, Vascular Endothelial Growth Factor A, Lymphatic Vessels, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Antibodies, Neutralizing, Human Umbilical Vein Endothelial Cells, MCF-7 Cells, Triple Negative Breast Neoplasms

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

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