Continuous inflammatory stimulation leads via metabolic plasticity to a pro-metastatic phenotype in triple-negative breast cancer cells II

Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that the continuous stimulation (6 weeks) of triple-negative breast tumor cells (TNBC) by the potent pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) had a robust effect on gene expression, demonstrating that the cancer cells have been skewed to strong pro-inflammatory phenotype. Moreover, continuous TNFα + IL-1β stimulation has reduced cell-to-cell contacts in the cancer cells and has induced metabolic plasticity in TNBC cells: this was exemplified by increase in active mitochondria area and elevations in the glycolytic as well as mitochondrial respiratory potential of the cancer cells (OXPHOS). Glycolysis has induced p65 activation and has led to increased transcription and expression of pro-metastatic chemokines such as CXCL8, CXCL1 and CCL2 and sICAM-1; agreeing with the ability of these chemokines to induce the recruitment of deleterious myeloid cells to tumors, mainly inhibition of glycolysis has given rise to reduced monocytic cell migration, in vitro and in vivo, in response to cancer cell supernatants obtained following continuous TNFα + IL-1β stimulation. Such inflammation-induced metabolic plasticity, which promotes metastatic cascades in TNBC, may have important clinical implications in the treatment of TNBC patients To explore this important aspect of inflammation-driven effects on breast tumor cells, we chose to study the most aggressive subtype of breast cancer, namely triple-negative breast cancer (TNBC). The TNBC subtype account for 15-20% of breast cancer cases, demonstrating high degree of recurrence and poor survival [19-21]. In view of the large versatility of pro-metastatic functions demonstrated by TNBC cells, it was of major interest to determine if a continuous stimulation by TNFα + IL-1β will further potentiate some of these activities or even lead to acquisition of novel pro-metastatic capabilities by TNBC cells.