title: Rapid dissemination of RET-transgene-driven melanoma in the presence of non-obese diabetic alleles: Critical roles of Dectin-1 and Nitric-oxide synthase type 2.
abstract: Mice transgenic for the RET oncogene provide a remarkable model for investigating the mechanisms underlying the promotion and the development of melanoma. This model was established on the C57BL/6 genetic background. In the present study, we investigated an effect of the strongly proinflammatory and autoimmune genetic makeup of the non-obese diabetic (NOD) strain. We bred (NODxB6)F1 mice and backcrossed them with NOD mice. F1 mice and mice at subsequent generations of backcrossing showed marked acceleration of tumor development, in particular with a more frequent and earlier extension of the primary uveal melanoma. In close relation with this severe evolution, we observed a profound drop in Dectin-1 expression on CD11b(+)Ly6G(+) granulocytic myeloid cells correlating with an expansion of CD4(+)Foxp3(+) T regulatory cell and of interferon(IFN)γ-producing CD8(+) T cell subsets in tumors. IFNγ is a major inducer of the type 2 nitric-oxide synthase (Nos2) gene whose products are known to be tumorigenic. Germline inactivation of the Nos2 gene was associated with a dramatically improved tumor prognosis and a restoration of Dectin-1 expression on myeloid cells. Moreover, in vivo treatment of (NODxB6)F1.RET(+) mice with curdlan, a glucose polymer that binds Dectin-1, prevented tumor extension and was associated with marked reduction of the CD4(+)Foxp3(+) T cell subset. These observations highlight the (NODxB6)F1.RET(+) mice as a new model to investigate the role of the immune system in the host-tumor relationship and point to Dectin-1 and Nos2 as potentially promising therapeutic targets.
authors.affiliation: Inserm U1173 and University of Versailles Saint-Quentin, Montigny-le-Bretonneux, France; Inserm U1016, CNRS UMR8104, Institut Cochin and University Paris Descartes, Paris, France.
authors.forename: Emna
authors.initials: E
authors.lastname: Dabbeche-Bouricha
authors.affiliation: Inserm U1173 and University of Versailles Saint-Quentin , Montigny-le-Bretonneux, France.
authors.forename: Luiza M
authors.initials: LM
authors.lastname: Araujo
authors.affiliation: Nagoya University Graduate School of Medicine , Nagoya, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Inserm U1016, CNRS UMR8104, Institut Cochin and University Paris Descartes , Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
authors.affiliation: Inserm U1173 and University of Versailles Saint-Quentin, Montigny-le-Bretonneux, France; Ambroise Paré Hospital, Division of Genetics, Boulogne-Billancourt, France.
authors.forename: Henri-Jean
authors.initials: HJ
authors.lastname: Garchon
keywords: Dectin-1; NOD mouse; Nos2; RET; melanoma; myeloid cells