Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer.
Animals
Bone Marrow Cells
/ physiology
Breast Neoplasms
/ pathology
Cell Line, Tumor
Endothelial Progenitor Cells
/ physiology
Endothelium, Lymphatic
/ pathology
Female
Humans
Lymphangiogenesis
/ physiology
Lymphatic Metastasis
Lymphatic Vessels
/ pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, SCID
Myeloid Cells
/ physiology
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
05
12
2018
revised:
20
06
2019
accepted:
09
07
2019
pubmed:
20
8
2019
medline:
2
4
2020
entrez:
18
8
2019
Statut:
ppublish
Résumé
Lymphatic metastasis is a high-impact prognostic factor for mortality of breast cancer (BC) patients, and it directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECPs) derived from the bone marrow (BM). As BC recruits massive numbers of provascular myeloid cells, we hypothesized that M-LECPs, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypothesis, high levels of M-LECPs were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECPs coexpress lymphatic-specific, stem/progenitor and M2-type macrophage markers that indicate their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Using four orthotopic BC models, we show that mouse M-LECPs are similarly recruited to tumors and integrate into preexisting lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated BM cells, significantly increased metastatic burden in ipsilateral lymph nodes. These data support a causative role of BC-induced lymphatic progenitors in tumor lymphangiogenesis and suggest molecular targets for their inhibition.
Identifiants
pubmed: 31421071
pii: S0002-9440(19)30662-5
doi: 10.1016/j.ajpath.2019.07.006
pmc: PMC6892188
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2269-2292Subventions
Organisme : NCI NIH HHS
ID : R01 CA199649
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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