Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma

• Published in: Blood Vol. 123; no. 14; pp. 2189 - 2198
• Main Authors: Koch, Raphael, Demant, Martin, Aung, Thiha, Diering, Nina, Cicholas, Anna, Chapuy, Bjoern, Wenzel, Dirk, Lahmann, Marlen, Güntsch, Annemarie, Kiecke, Christina, Becker, Sabrina, Hupfeld, Timo, Venkataramani, Vivek, Ziepert, Marita, Opitz, Lennart, Klapper, Wolfram, Trümper, Lorenz, Wulf, Gerald G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.04.2014
• Subjects: Cell Count; Cell Proliferation; Clone Cells - pathology; Disease Progression; Exosomes - physiology; HEK293 Cells; Homeostasis - physiology; Humans; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Neoplastic Stem Cells - pathology; Protein Transport; Tumor Cells, Cultured; Wnt Signaling Pathway - physiology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-08-523886

Tumors are composed of phenotypically heterogeneous cell populations. The nongenomic mechanisms underlying transitions and interactions between cell populations are largely unknown. Here, we show that diffuse large B-cell lymphomas possess a self-organized infrastructure comprising side population (SP) and non-SP cells, where transitions between clonogenic states are modulated by exosome-mediated Wnt signaling. DNA methylation modulated SP–non-SP transitions and was correlated with the reciprocal expressions of Wnt signaling pathway agonist Wnt3a in SP cells and the antagonist secreted frizzled-related protein 4 in non-SP cells. Lymphoma SP cells exhibited autonomous clonogenicity and exported Wnt3a via exosomes to neighboring cells, thus modulating population equilibrium in the tumor. •Diffuse large B-cell lymphomas are composed of clonogenic side population (SP) cells and non-SP cells organized in a dynamic equilibrium.•Exosome-mediated Wnt signaling modulates transitions of cell states and tumor progression amenable to drug targeting.