Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

Autor: Yasmine Touil, Pascaline Segard, Pierre Formstecher, Jerome Vandomme, Pauline Ostyn, Pilar Flamenco, Raja El Machhour, Séverine Bégard, Renata Polakowska, Bernadette Masselot, Nuria Kotecki
Přispěvatelé: Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This research was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM), the Institut National du Cancer (National Cancer Institute) of France and the SILAB-Jean Paufique Corporate Foundation. Y. Touil was supported by the Institut Pour la Recherche sur le Cancer de Lille (IRCL) and by SIRIC ONCOLille R. El Machhour was supported by the Ligue Nationale Contre le Cancer. P. Flamenco was supported by the CPER (Contrat de Plan Etat/Région) program of the Nord - Pas de Calais region. P. Ostyn's graduate study was financed by CHRU Lille and the Region Nord-Pas de Calais, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dupuis, Christine
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: Cell Communication and Signaling : CCS
Cell Commun Signal
Cell Commun Signal, 2014, 12 (1), pp.52. ⟨10.1186/PREACCEPT-1668207151340493⟩
ISSN: 1478-811X
DOI: 10.1186/PREACCEPT-1668207151340493⟩
Popis: International audience; : 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.
Databáze: OpenAIRE
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