Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

• Published in: Molecular oncology Vol. 12; no. 9; pp. 1540 - 1558
• Main Authors: Prasmickaite, Lina, Tenstad, Ellen M., Pettersen, Solveig, Jabeen, Shakila, Egeland, Eivind V., Nord, Silje, Pandya, Abhilash, Haugen, Mads H., Kristensen, Vessela N., Børresen‐Dale, Anne‐Lise, Engebråten, Olav, Mælandsmo, Gunhild M.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2018; Wiley Open Access; John Wiley and Sons Inc; Wiley
• Subjects: Antibiotics; Blood & organ donations; Breast cancer; Cancer therapies; Cell adhesion & migration; Cell proliferation; Chemoresistance; Clinical medical disciplines: 750; Cytokines; Epidermal growth factor; Experiments; Gene expression; Granulocytes; Inflammation; Klinisk medisinske fag: 750; Laboratory animals; Macrophages; Medical disciplines: 700; Medical prognosis; Medisinske Fag: 700; Mesenchyme; Metastases; Metastasis; Monocytes; Myeloid cells; Oncology: 762; Onkologi: 762; Proteins; S100A4; S100A4 protein; Therapeutic targets; tumor microenvironment; Tumors; tumor‐associated macrophages; tumor–stroma interactions; VDP; United Kingdom > UK; United States > US; Norway; tumor-stroma interactions; breast cancer; S100A4; cytokines; tumor microenvironment; tumor-associated macrophages
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12319

The tumor microenvironment (TME) may influence both cancer progression and therapeutic response. In breast cancer, particularly in the aggressive triple‐negative/basal‐like subgroup, patient outcome is strongly associated with the tumor's inflammatory profile. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells in the TME, shown to be linked to poor prognosis and therapeutic resistance. In this study, we investigated the effect of the metastasis‐ and inflammation‐associated microenvironmental factor S100A4 on breast cancer cells (BCCs) of different subtypes and explored their further interactions with myeloid cells. We demonstrated that extracellular S100A4 activates BCCs, particularly the basal‐like subtype, to elevate secretion of pro‐inflammatory cytokines. The secreted factors promoted conversion of monocytes to TAM‐like cells that exhibited protumorigenic activities: stimulated epithelial–mesenchymal transition, proliferation, chemoresistance, and motility in cancer cells. In conclusion, we have shown that extracellular S100A4 instigates a tumor‐supportive microenvironment, involving a network of cytokines and TAM‐like cells, which was particularly characteristic for basal‐like BCCs and potentiated their aggressive properties. The S100A4–BCC–TAM interaction cascade could be an important contributor to the aggressive behavior of this subtype and should be further explored for therapeutic targeting. Aggressive basal‐like breast cancer cells (BCCs) elevate secretion of numerous pro‐inflammatory cytokines in response to the S100A4 protein present in the tumor microenvironment (TME). The secreted factors convert monocytes into tumor‐associated macrophages (TAMs), which promote epithelial–mesenchymal transition (EMT) and stimulate aggressive functions (proliferation, chemoresistance, and motility) in BCCs. The S100A4–BCC–TAM interaction cascade can be an important contributor to the aggressive behavior of basal‐like breast cancer.