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

// Adam R. Wolfe 1, 2 , Nicholaus J Trenton 5 , Bisrat G. Debeb 1, 2 , Richard Larson 1, 2 , Brian Ruffell 6 , Khoi Chu 4 , Walter Hittelman 4 , Michael Diehl 5 , Jim M Reuben 1 , Naoto T. Ueno 1, 3 , Wendy A. Woodward 1, 2 1 MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Bioengineering, Rice University, Houston, TX, USA 6 Department 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.