Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands.
Cell Line
Cell Line, Tumor
Cell Movement
/ drug effects
Cells, Cultured
Chemokines
/ metabolism
Culture Media, Conditioned
/ chemistry
Cytokines
/ metabolism
Female
Humans
Ligands
MCF-7 Cells
Neutrophil Infiltration
/ drug effects
Neutrophils
/ metabolism
Receptors, Interleukin-8B
/ metabolism
Transforming Growth Factor beta
/ metabolism
Triple Negative Breast Neoplasms
/ metabolism
CXCL1/2/3
TGF-β
TNBC
breast cancer
chemotaxis
neutrophil
tumor spheroid
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
28
01
2021
accepted:
11
03
2021
entrez:
29
4
2021
pubmed:
30
4
2021
medline:
21
10
2021
Statut:
epublish
Résumé
Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO (CXCL1/2/3) chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.
Identifiants
pubmed: 33912188
doi: 10.3389/fimmu.2021.659996
pmc: PMC8071875
doi:
Substances chimiques
CXCR2 protein, human
0
Chemokines
0
Culture Media, Conditioned
0
Cytokines
0
Ligands
0
Receptors, Interleukin-8B
0
Transforming Growth Factor beta
0
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
659996Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK042303
Pays : United States
Informations de copyright
Copyright © 2021 SenGupta, Hein, Xu, Zhang, Konwerski, Li, Johnson, Cai, Smith and Parent.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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