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

Oncotarget. 2016 Dec 13;7(50):82482-82492. doi: 10.18632/oncotarget.12694.


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.

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Coculture Techniques
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-6 / metabolism*
  • Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Macrophage Colony-Stimulating Factor / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mesenchymal Stem Cells / immunology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local
  • Paracrine Communication*
  • Phosphorylation
  • RAW 264.7 Cells
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Time Factors
  • Tumor Burden
  • Tumor Microenvironment


  • Antineoplastic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • IL6 protein, human
  • Interleukin-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Macrophage Colony-Stimulating Factor