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.
authors.affiliation: 1] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Chemical and Biomolecular Engineering, School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Esak
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Kideok
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Niranjan B
authors.initials: NB
authors.lastname: Pandey
authors.affiliation: 1] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Chemical and Biomolecular Engineering, School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA [3] Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D000077592:Maraviroc; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000636:Aminosalicylic Acids; D057134:Antibodies, Neutralizing; D001557:Benzenesulfonates; D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D003510:Cyclohexanes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D000077592:Maraviroc; D050796:STAT3 Transcription Factor; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C497442:HIF1A protein, human; C508600:IL6 protein, human; C520337:NSC 74859; C494086:STAT3 protein, human; C467484:VEGFA protein, human