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Soluble Tumor Necrosis Factor Receptors Shed by Breast Tumor Cells Inhibit Macrophage Chemotaxis

Soluble Tumor Necrosis Factor Receptors Shed by Breast Tumor Cells Inhibit Macrophage Chemotaxis

Stephen Lee Rego, Muthulekha Swamydas, Amritha Kidiyoor, Rachel Helms, Alexander De Piante, Amanda L Lance, Pinku Mukherjee, Didier Dréau

J Interferon Cytokine Res. 2013 Nov;33(11):672-81.

PMID: 23777205

Abstract:

Breast tumor cells alter their microenvironment in part through the expression of protumor molecules that influence macrophages during tumor progression and metastasis. Macrophage recruitment is stimulated by chemotactic factors, including tumor necrosis factor alpha (TNF-α), which also stimulates the cytotoxic/tumor cell killing macrophage phenotype. Through TNF-α converting enzyme (TACE/ADAM17) activities, breast tumor cells shed membrane-bound proteins, including their TNF receptors (sTNFR1/2), which serve as decoys sequestering TNF-α and preventing TNF-α-driven apoptosis of tumor cells, thereby decreasing TNF-α bioavailability. Here we investigated the levels of sTNFRs shed by breast tumor cells and determined the effects of shed sTNFRs on macrophage migration toward TNF-α. TNF-α and sTNFRs concentrations were measured in murine normal epithelial, stromal, and mammary tumor cells. The migration of murine macrophages towards TNF-α in the presence of tumor derived soluble factors (TDSFs) shed by TACE was determined. TNF-α concentrations secreted by tumor and normal epithelial cells were below the detection limit contrasting with stromal cells, especially macrophages, which expressed higher levels of TNF-α (P<0.001). Regardless of the cell tested, treatment with the TACE inhibitor TAPI-0 led to a significant decrease in sTNFR2 shed (P<0.05). The dose-dependent macrophage migration toward TNF-α prevented by incubation with TDSFs was not observed with TDSFs collected following TAPI-0 treatment (P<0.05). Furthermore, the TNF-α-driven increased pAkt expression in macrophage was inhibited by TACE shed TDSFs (P<0.05). These results highlight the role of tumor-shed sTNFRs in TNF-α -driven macrophage chemotaxis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP163958734	TAPI-0		163958-73-4	Price

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