Continuous Inflammatory Stimulation Leads via Metabolic Plasticity to a Prometastatic Phenotype in Triple-Negative Breast Cancer Cells

Abstract

Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that a continuous stimulation (~6 weeks) of triple-negative breast tumor cells (TNBC) by the proinflammatory cytokines tumor necrosis factor α (TNFα) + interleukin 1β (IL-1β) changed the expression of hundreds of genes, skewing the cells towards a proinflammatory phenotype. While not affecting stemness, the continuous TNFα + IL-1β 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 TNFα + IL-1β stimulation has promoted in a glycolysis-dependent manner the activation of p65 (NF-kB), 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 TNFα + IL-1β 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.

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

“…To this end, WT-PD-L1-BT and WT-PD-L1-MDA TNBC cells were cultured in similar numbers to CTRL-vector cells for four or five days. Tumor cell growth was determined at these two time points by cell counting, and not by XTT/MTT assays, as the latter may provide evidence to increased metabolic activities and not necessarily to tumor growth, as we have shown in our previous study [ 40 ].…”

“…To this end, WT-PD-L1-BT and WT-PD-L1-MDA TNBC cells were cultured in similar numbers to CTRL-vector cells for four or five days. Tumor cell growth was determined at these two time points by cell counting, and not by XTT/MTT assays, as the latter may provide evidence to increased metabolic activities and not necessarily to tumor growth, as we have shown in our previous study [40]. Based on reports demonstrating that soluble PD-1 is connected to an advanced disease state in different malignancies and is functional in activating PD-L1 (as indicated for example by regulation of immune activities) [35][36][37][38][39], the effects of PD-1 in both systems were determined by exposing the cancer cells to a soluble PD-1 protein.…”

Precision unveiled: Synergistic genomic landscapes in breast cancer—Integrating single‐cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics

“…Their reciprocal regulation, particularly via the MIF‐(CD74 + CXCR4) pathway—intricately linked to inflammation 63 —is noteworthy. As previously delineated, tumor cells can exploit inflammatory responses as a growth impetus 61 . This interplay might shed light on the observed distribution patterns of monocytes and T cells within tumors.…”

“…The prevalent monocyte distribution can be attributed to the chemoattractive properties of CCL2, which beckon monocyte migration towards the tumor. This phenomenon might potentiate tumor growth, propelled by an inflammatory cascade that orchestrates monocyte recruitment and their subsequent differentiation into tumor‐associated macrophages 61 . Interestingly, T‐cell concentrations trend higher in breast malignancies that are less aggressive, whereas cancers with heightened malignancy display diminished T‐cell levels 62 .…”

Sobrepeso, obesidad y cáncer de mama

“…Este es un factor paracrino considerado como agente anticarcinogénico, ya que inhibe la transformación maligna Las adipocitocinas que vinculan la obesidad con el cáncer de mama incluyen interleucina-1 y leptina. Estas tienen efectos importantes en la hematopoyesis, reproducción, inmunidad y crecimiento tumoral (17). La sobreexpresión de SHIP2 está fuertemente relacionada con el aumento de las concentraciones de leptina.…”