Journal
CELL COMMUNICATION AND SIGNALING
Volume 12, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12964-014-0052-z
Keywords
Cancer stem cells; Quiescence; Label-retaining cell; Melanoma; TNF
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Institut National du Cancer (National Cancer Institute) of France
- SILAB-Jean Paufique Corporate Foundation
- Institut Pour la Recherche sur le Cancer de Lille (IRCL)
- SIRIC ONCOLille
- Ligue Nationale Contre le Cancer
- CPER (Contrat de Plan Etat/Region) program of the Nord - Pas de Calais region
- CHRU Lille
- Region Nord-Pas de Calais
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Background: It 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. Results: Using 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. Conclusions: We 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.
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