Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

Evan N Cohen,Hui Gao,Sendurai A Mani,Raul J Garza,Qiong Wu,Simone Anfossi,James M Reuben,Sanda Tin,Naoto T Ueno,Antonio Giordano,Raja Luthra,Neelima G Reddy,Denise A Croix,Wendy A Woodward,Michal Mego,Bisrat Debeb,Massimo Cristofanilli,Savitri Krishnamurthy

doi:10.1371/journal.pone.0132710

Abstract

Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

Highlights

Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer, characterized by diffuse erythema and edema of the breast that is often mistaken for mastitis
We have recently demonstrated that detection of any of these epithelial-to-mesenchymal transition (EMT)-related transcription factors (EMT-TFs) or TGM2 in the peripheral blood of breast cancer patients can serve as a surrogate for circulating tumor cells (CTC) in breast cancer patients [16]
The number of patients is small, higher numbers of tumor necrosis factor (TNF)-T cells were associated with a greater ability to detect EMT-CTC in breast cancer patients

Summary

Introduction

Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer, characterized by diffuse erythema and edema of the breast that is often mistaken for mastitis. IBC may present with an augmented cellular immune response to tumor antigen and showed that IBC patients have normal delayed-type hypersensitivity reactions to standard recall antigens and breast tumor lysate [4] The effect of this postulated immune response on tumor cells and their metastatic potential is only beginning to be explored. Activated immune cells are capable of producing factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and transforming growth factor (TGF)-β that induce epithelial-to-mesenchymal transition (EMT). These characteristics suggest that immune cells may induce an EMT in IBC

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Results

Conclusion