title: B-1 lymphocytes increase metastatic behavior of melanoma cells through the extracellular signal-regulated kinase pathway.
abstract: Increasing evidence indicates that tumors require a constant influx of myelomonocytic cells to support their malignant behavior. This is caused by tumor-derived factors, which recruit and induce functional differentiation of myelomonocytic cells, most of which are macrophages. Although myeloid lineages are the classical precursors of macrophages, B-lymphoid lineages such as B-1 cells, a subset of B-lymphocytes found predominantly in pleural and peritoneal cavities, are also able to migrate to inflammatory sites and differentiate into mononuclear phagocytes exhibiting macrophage-like phenotypes. Here we examined the interplay of B-1 cells and tumor cells, and checked whether this interaction provides signals to influence melanoma cells metastases. Using in vitro coculture experiments we showed that B16, a murine melanoma cell line, and B-1 cells physically interact. Moreover, interaction of B16 with B-1 cells leads to up-regulation of metastasis-related gene expression (MMP-9 and CXCR-4), increasing its metastatic potential, as revealed by experimental metastases assays in vivo. We also provide evidence that B16 cells exhibit markedly up-regulated phosphorylation of the extracellular signal-regulated kinase (ERK) when cocultured with B-1 cells. Inhibition of ERK phosphorylation induced by B-1 cells with inhibitors of MEK1/2 strongly suppressed the induction of MMP-9 and CXCR-4 mRNA expression and impaired the increased metastatic behavior of B16. In addition, constitutive levels of ERK1/2 phosphorylation in B-1 cells are necessary for their commitment to affect the metastatic potential of B16 cells. Our findings show for the first time that B-1 lymphocytes can contribute to tumor cell properties required for invasiveness during metastatic spread.
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, Rua Botucatu 862, 04023-062, São Paulo, Brazil.
authors.forename: Elizabeth Cristina
authors.initials: EC
authors.lastname: Pérez
authors.forename: Joel
authors.initials: J
authors.lastname: Machado
authors.forename: Fabiana
authors.initials: F
authors.lastname: Aliperti
authors.forename: Edna
authors.initials: E
authors.lastname: Freymüller
authors.forename: Mario
authors.initials: M
authors.lastname: Mariano
authors.forename: José Daniel
authors.initials: JD
authors.lastname: Lopes
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases