Abstract
BackgroundIt is well established that inflammation promotes cancer, including melanoma, although the exact mechanisms involved are less known. In this study, we tested the hypothesis that inflammatory factors affect the cancer stem cell (CSC) compartment responsible for tumor development and relapse.ResultsUsing an inducible histone 2B-GFP fusion protein as a tracer of cell divisional history, we determined that tumor necrosis factor (TNF), which is a classical pro-inflammatory cytokine, enlarged the CSC pool of GFP-positive label-retaining cells (LRCs) in tumor-like melanospheres. Although these cells acquired melanoma stem cell markers, including ABCB5 and CD271, and self-renewal ability, they lost their capacity to differentiate, as evidenced by the diminished MelanA expression in melanosphere cells and the loss of pigmentation in a skin equivalent model of human melanoma. The undifferentiated cell phenotype could be reversed by LY294002, which is an inhibitor of the PI3K/AKT signaling pathway, and this reversal was accompanied by a significant reduction in CSC phenotypic markers and functional properties. Importantly, the changes induced by a transient exposure to TNF were long-lasting and observed for many generations after TNF withdrawal.ConclusionsWe conclude that pro-inflammatory TNF targets the quiescent/slow-cycling melanoma SC compartment and promotes PI3K/AKT-driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal. This TNF effect is maintained and transferred to descendants of LRC CSCs and is manifested in the absence of TNF, suggesting that a transient exposure to inflammatory factors imprints long-lasting molecular and/or cellular changes with functional consequences long after inflammatory signal suppression. Clinically, these results may translate into an inflammation-triggered accumulation of quiescent/slow-cycling CSCs and a post-inflammatory onset of an aggressive tumor.
Highlights
It is well established that inflammation promotes cancer, including melanoma, the exact mechanisms involved are less known
Detection of label-retaining melanoma cancer stem cells in vitro Cancer stem cells (CSCs), similar to normal adult stem cells (SCs), remain quiescent most of the time and only infrequently enter the cell cycle to self-renew and to produce progeny committed to differentiation, composing most the tumor mass
At day 9, 2.8% ± 1.8 of cells still retained their labels (Figure 1B, C); all cells eventually lost their labels, indicating that the monolayer culture conditions are incompatible with long-term cellular quiescence and that all cells divide, some are slower than others
Summary
It is well established that inflammation promotes cancer, including melanoma, the exact mechanisms involved are less known. Despite advances in melanoma research and drug development, 10-20% of clinically disease-free patients relapse 5–10 years following an initial treatment [1,2] This phenomenon, which is known as tumor dormancy [3], has been related to the existence of the incidence of cancer and chronic inflammation [9,10] prompt us to study whether pro-inflammatory Tumor Necrosis Factor (TNF) is involved in the phenotypic switch of quiescent tumor cells into their active proliferative state in melanoma. By a serial transplantation of SE-tumor cells using sphere-forming assays, we found that the tumor-founding cells maintain these TNFinduced properties for generations after first exposure and that this activity may be mediated by the PI3K/AKT signaling pathway
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