Continuous Inflammatory Stimulation Leads Via Metabolic Plasticity To A Prometastatic Phenotype In Triple-Negative Breast Cancer Cells

Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that a continuous stimulation (similar to 6 weeks) of triple-negative breast tumor cells (TNBC) by the proinflammatory cytokines tumor necrosis factor alpha (TNF alpha) + interleukin 1 beta (IL-1 beta) changed the expression of hundreds of genes, skewing the cells towards a proinflammatory phenotype. While not affecting stemness, the continuous TNF alpha + IL-1 beta stimulation has increased tumor cell dispersion and has induced a hybrid metabolic phenotype in TNBC cells; this phenotype was indicated by a transcription-independent elevation in glycolytic activity and by increased mitochondrial respiratory potential (OXPHOS) of TNBC cells, accompanied by elevated transcription of mitochondria-encoded OXPHOS genes and of active mitochondria area. The continuous TNF alpha + IL-1 beta stimulation has promoted in a glycolysis-dependent manner the activation of p65 (NF-kappa B), and the transcription and protein expression of the prometastatic and proinflammatory mediators sICAM-1, CCL2, CXCL8 and CXCL1. Moreover, when TNBC cells were stimulated continuously by TNF alpha + IL-1 beta in the presence of a glycolysis inhibitor, their conditioned media had reduced ability to recruit monocytes and neutrophils in vivo. Such inflammation-induced metabolic plasticity, which promotes prometastatic cascades in TNBC, may have important clinical implications in treatment of TNBC patients.