Tumor-Stroma-Inflammation Networks Promote Pro-metastatic Chemokines and Aggressiveness Characteristics in Triple-Negative Breast Cancer.
Biomarkers
Cancer-Associated Fibroblasts
/ metabolism
Cell Line, Tumor
Chemokines
/ metabolism
Disease Progression
Female
Humans
Inflammation
/ complications
Inflammation Mediators
/ metabolism
Interleukin-1beta
/ metabolism
Mesenchymal Stem Cells
Neovascularization, Pathologic
/ metabolism
Signal Transduction
Stromal Cells
/ metabolism
Triple Negative Breast Neoplasms
/ etiology
Tumor Microenvironment
Tumor Necrosis Factor-alpha
/ metabolism
CCL2
CCL5
CXCL8
cancer-associated fibroblasts
interleukin 1β
mesenchymal stem cells
triple-negative breast cancer
tumor necrosis factor α
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2019
2019
Historique:
received:
28
07
2018
accepted:
21
03
2019
entrez:
30
4
2019
pubmed:
30
4
2019
medline:
11
8
2020
Statut:
epublish
Résumé
The tumor microenvironment (TME) plays key roles in promoting disease progression in the aggressive triple-negative subtype of breast cancer (TNBC; Basal/Basal-like). Here, we took an integrative approach and determined the impact of tumor-stroma-inflammation networks on pro-metastatic phenotypes in TNBC. With the TCGA dataset we found that the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β), as well as their target pro-metastatic chemokines CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES) were expressed at significantly higher levels in basal patients than luminal-A patients. Then, we found that TNFα- or IL-1β-stimulated co-cultures of TNBC cells (MDA-MB-231, MDA-MB-468, BT-549) with mesenchymal stem cells (MSCs) expressed significantly higher levels of CXCL8 compared to non-stimulated co-cultures or each cell type alone, with or without cytokine stimulation. CXCL8 was also up-regulated in TNBC co-cultures with breast cancer-associated fibroblasts (CAFs) derived from patients. CCL2 and CCL5 also reached the highest expression levels in TNFα/IL-1β-stimulated TNBC:MSC/CAF co-cultures. The elevations in CXCL8 and CCL2 expression partly depended on direct physical contacts between the tumor cells and the MSCs/CAFs, whereas CCL5 up-regulation was entirely dependent on cell-to-cell contacts. Supernatants of TNFα-stimulated TNBC:MSC "Contact" co-cultures induced robust endothelial cell migration and sprouting. TNBC cells co-cultured with MSCs and TNFα gained migration-related morphology and potent migratory properties; they also became more invasive when co-cultured with MSCs/CAFs in the presence of TNFα. Using siRNA to CXCL8, we found that CXCL8 was significantly involved in mediating the pro-metastatic activities gained by TNFα-stimulated TNBC:MSC "Contact" co-cultures: angiogenesis, migration-related morphology of the tumor cells, as well as cancer cell migration and invasion. Importantly, TNFα stimulation of TNBC:MSC "Contact" co-cultures
Identifiants
pubmed: 31031757
doi: 10.3389/fimmu.2019.00757
pmc: PMC6473166
doi:
Substances chimiques
Biomarkers
0
Chemokines
0
IL1B protein, human
0
Inflammation Mediators
0
Interleukin-1beta
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
757Références
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