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

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.

Macrophages Enhance Migration in Inflammatory Breast Cancer Cells via RhoC GTPase Signaling

“…Our results are also in keeping with other recent studies that profiled the importance of macrophages in IBC404142. Cohen et al .…”

“…Cohen et al . studied the epithelial-mesenchymal transition in IBC cell lines and found IL-6 to be one essential driver of the transition as measured by qRT-PCR of a standard gene panel40. Mohamed et al .…”

Three-dimensional culture systems in cancer research: Focus on tumor spheroid model

“…Upon obstructing lymphatic vessels, tumor emboli prevent proper drainage of the lymph fluid, causing skin reddening and painful swelling of breast tissue (Vermeulen et al , 2010; Lehman et al , 2013). IBC cells display high ALDH positivity, express high levels of E-cadherin, and interestingly, continue to express elevated levels of epithelial cell markers like E-cadherin, while gaining mesenchymal and stem-like characteristics (Nguyen et al , 2006; Charafe-jauffret et al , 2010; Cohen et al , 2015). In addition, activation of anti-apoptotic and antioxidant signaling cascades allow the IBC cells to survive in the presence of various cell death signals, leading to therapeutic resistance (Thomas et al , 2011; Allensworth et al , 2013; Williams et al , 2013; Price et al , 2015; Evans, 2016).…”

Secretome of tumor-associated leukocytes augment epithelial-mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-κB/p65 signaling pathway

“…In addition, expression of IL-4 and IL-17 found to indirectly induce bronchial-EMT via synergized action with TGF-β1 [39]. Furthermore, a study showed that the combination of TNF-α, IL-6, and TGF-β and cytokines released by activated immune cells augment aggressiveness of inflammatory breast cancer cells via the EMT process [40]. These data support our present results that a synergism among the secreted cytokines of TALs isolated from pLNs breast cancer patients stimulates the EMT program.…”