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Stem Cell Res Ther. 2015 May 1;6:87. doi: 10.1186/s13287-015-0080-7.

Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway.

Author information

1
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. christina.katanov@weizmann.ac.il.
2
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. slerrer@gmail.com.
3
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. yulialiub@gmail.com.
4
Department of Pathology, Tel Aviv Sourasky Medical Center and the Sackler School of Medicine, Tel Aviv University, 6 Weizmann Street, Tel Aviv, 64239, Israel. treleox2@yahoo.com.
5
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. tzipi@post.tau.ac.il.
6
Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, 5262100, Israel. bar.jair@gmail.com.
7
Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, 5262100, Israel. rotemfe@gmail.com.
8
Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, 5262100, Israel. iris.kamer@gmail.com.
9
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. galisoria@gmail.com.
10
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. kahanihadar@gmail.com.
11
Department of Medicine and Pharmacology, Robert Wood Johnson Medical School and Graduate School of Biomedical Sciences, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA. banerjed@cinj.rutgers.edu.
12
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, P.O. Box 39040, Tel Aviv, 6997801, Israel. aditbb@tauex.tau.ac.il.

Abstract

INTRODUCTION:

Breast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES).

METHODS:

Chemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-α (and IL-1β). The roles of AP-1 and NF-κB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers.

RESULTS:

TNF-α (and IL-1β) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-α (and IL-1β) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-α-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF-κB but not via the AP-1 pathway. Exposure of MSCs to TNF-α led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors.

CONCLUSIONS:

Our novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-κB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies.

PMID:
25928089
PMCID:
PMC4469428
DOI:
10.1186/s13287-015-0080-7
[Indexed for MEDLINE]
Free PMC Article

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