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Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression
Authors: Diaz-Valdes, N. (Nancy)
Basagoiti, M. (María)
Dotor, J. (Javier)
Aranda, F. (Fernando)
Monreal, I. (Iñaki)
Riezu-Boj, J.I. (José Ignacio)
Borras-Cuesta, F. (Francisco)
Sarobe, P. (Pablo)
Feijoo, E. (Esperanza)
Keywords: Chemokine CCL2/biosynthesis
Interleukin-10/biosynthesis
Melanoma/immunology
Transforming Growth Factor beta1/pharmacology
Issue Date: 2011
Publisher: American Association for Cancer Research
Publisher version: http://cancerres.aacrjournals.org/content/71/3/812
ISSN: 0008-5472
Citation: Diaz-Valdes N, Basagoiti M, Dotor J, Aranda F, Monreal I, Riezu-Boj JI, et al. Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Cancer Res 2011 Feb 1;71(3):812-821.
Abstract
Melanoma progression is associated with the expression of different growth factors, cytokines, and chemokines. Because TGFβ1 is a pleiotropic cytokine involved not only in physiologic processes but also in cancer development, we analyzed in A375 human melanoma cells, the effect of TGFβ1 on monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) expression, two known factors responsible for melanoma progression. TGFβ1 increased the expression of MCP-1 and IL-10 in A375 cells, an effect mediated by the cross-talk between Smad, PI3K (phosphoinositide 3-kinase)/AKT, and BRAF-MAPK (mitogen activated protein kinase) signaling pathways. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms. When using in vitro, the TGFβ1-blocking peptide P144, TGFβ1-dependent Smad3 phosphorylation, and expression of MCP-1 and IL-10 were inhibited. In vivo, treatment of A375 tumor-bearing athymic mice with P144 significantly reduced tumor growth, associated with a lower macrophage infiltrate and decreased intratumor MCP-1 and VEGF levels, as well as angiogenesis. Finally, in C57BL/6 mice with B16-OVA melanoma tumors, when administered with immunotherapy, P144 decreased tumor growth and intratumor IL-10 levels, linked to enhanced activation of dendritic cells and natural killer cells, as well as anti-OVA T-cell responses. These results show new effects of TGFβ1 on melanoma cells, which promote tumor progression and immunosuppression, strongly reinforcing the relevance of this cytokine as a molecular target in melanoma.
Permanent link: http://hdl.handle.net/10171/21584
Appears in Collections:DA - CUN - Medicina interna - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Virología - Artículos de revista
DA - Medicina - Medicina Interna - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Inmunología experimental - Artículos de revista

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