Oncotarget

Research Papers:

Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models

Adam R. Wolfe, Nicholaus J Trenton, Bisrat G. Debeb, Richard Larson, Brian Ruffell, Khoi Chu, Walter Hittelman, Michael Diehl, Jim M Reuben, Naoto T. Ueno and Wendy A. Woodward _

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Oncotarget. 2016; 7:82482-82492. https://doi.org/10.18632/oncotarget.12694

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Abstract

Adam R. Wolfe1,2, Nicholaus J Trenton5, Bisrat G. Debeb1,2, Richard Larson1,2, Brian Ruffell6, Khoi Chu4, Walter Hittelman4, Michael Diehl5, Jim M Reuben1, Naoto T. Ueno1,3, Wendy A. Woodward1,2

1MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

5Department of Bioengineering, Rice University, Houston, TX, USA

6Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Correspondence to:

Wendy A. Woodward, email: wwoodward@mdanderson.org

Keywords: inflammatory breast cancer, macrophages, mesenchymal stem cells, IL-6, statins

Received: August 23, 2016     Accepted: October 06, 2016     Published: October 15, 2016

ABSTRACT

Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti-CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs.


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