title: Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression.
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.
authors.affiliation: Universidad de Navarra, Centro de Investigación Médica Aplicada, Área de Hepatología y Terapia Génica, Pamplona, Spain.
authors.forename: Nancy
authors.initials: N
authors.lastname: Díaz-Valdés
authors.forename: María
authors.initials: M
authors.lastname: Basagoiti
authors.forename: Javier
authors.initials: J
authors.lastname: Dotor
authors.forename: Fernando
authors.initials: F
authors.lastname: Aranda
authors.forename: Iñaki
authors.initials: I
authors.lastname: Monreal
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Riezu-Boj
authors.forename: Francisco
authors.initials: F
authors.lastname: Borrás-Cuesta
authors.forename: Pablo
authors.initials: P
authors.lastname: Sarobe
authors.forename: Esperanza
authors.initials: E
authors.lastname: Feijoó
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D051057:Proto-Oncogene Proteins c-akt