Anti-CXCL15 monoclonal antibody, clone FQS25570

Metastasis is the most devastating aspect of cancer, however we know very little about the mechanisms of local invasion, the earliest step of metastasis. During tumor growth CD11b(+)Gr1(+) cells, known also as MDSCs, have been shown to promote tumor progression by a wide spectrum of effects that suppress the anti-tumor immune response. In addition to immunosuppression, CD11b(+)Gr1(+) cells promote metastasis by mechanisms that are currently unknown. CD11b(+)Gr1(+) cells localize near fibroblasts, which remodel the ECM and leave tracks for collective cell migration of carcinoma cells. In this study we discovered that CD11b(+)Gr1(+) cells promote invasion of mammary carcinoma cells by increasing fibroblast migration. This effect was directed by secreted factors derived from CD11b(+)Gr1(+) cells. We have identified several CD11b(+)Gr1(+) cell secreted proteins that activate fibroblast migration, including CXCL11, CXCL15, FGF2, IGF-I, IL1Ra, Resistin, and Shh. The combination of CXCL11 and FGF2 had the strongest effect on fibroblast migration that is associated with Akt1 and ERK1/2 phosphorylation. Analysis of subsets of CD11b(+)Gr1(+) cells identified that CD11b(+)Ly6C(high)Ly6G(low) cells increase fibroblast migration more than other myeloid cell populations. Additionally, tumor-derived CD11b(+)Gr1(+) cells promote fibroblast migration more than splenic CD11b(+)Gr1(+) cells of tumor-bearing mice. While TGF beta signaling in fibroblasts does not regulate their migration toward CD11b(+)Gr1(+) cells, however deletion of TGF beta receptor II on CD11b(+)Gr1(+) cells downregulates CXCL11, Shh, IGF1 and FGF2 resulting in reduced fibroblast migration. These studies show that TGF beta signaling in CD11b(+)Gr1(+) cells promotes fibroblast directed carcinoma invasion and suggests that perivascular CD11b(+)Ly6C(high)Ly6G(low) cells may be the stimulus for localized invasion leading to metastasis.

A major cause of preterm labor in pregnant women is intra-amniotic infection, which is mediated by an inflammatory process. Hydrogen sulfide (H2S), a gaseous transmitter, has been implicated to be involved in inflammatory responses. We sought to investigate whether H2S affects infectious preterm birth using the mouse model of lipopolysaccharides (LPS)induced preterm birth. Administration of LPS at 0.4 mg/kg with two injections intraperitoneally (i.p.) on gestational day 14.5 induced preterm labor. LPS significantly increased leukocyte infiltration in uterus, stimulated the expression of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), IL-6, tumor necrosis factor a (TNF-alpha), CCL2 and CXCL15 in myometrium. Administration of NaHS (i.p.) delayed the onset of labor induced by LPS in a dose-dependent manner. NaHS prevented leukocyte infiltration into intrauterine tissues and inhibited the production of pro-inflammatory cytokines in myometrium and decreased the levels of these cytokines in maternal circulation. H2S also decreased LPS-activated extracellular signal-regulated kinase (ERK) 1/2/nuclear factor (NF)-kappa B signaling pathways in myometrium. This study provides new in vivo evidence for the roles of H2S in attenuating inflammation, and a potential novel therapeutic strategy for infection-related preterm labor.