Metastasis is the primary cause of cancer death. Weichand et al. describe a new mechanism explaining how tumor-associated macrophages contribute to metastatic spread, which involves promoting tumor lymphangiogenesis via S1P receptor 1 and the NLRP3 inflammasome.

Tumor-immune cell interactions shape the immune cell phenotype, with microRNAs (miRs) being crucial components of this crosstalk. How they are transferred and how they affect their target landscape, especially in tumor-associated macrophages (TAMs), is largely unknown. Here we report that breast cancer cells have a high constitutive expression of miR-375, which is released as a non-exosome entity during apoptosis. Deep sequencing of the miRome pointed to enhanced accumulation of miR-375 in TAMs, facilitated by the uptake of tumor-derived miR-375 via CD36. In macrophages, miR-375 directly targets TNS3 and PXN to enhance macrophage migration and infiltration into tumor spheroids and in tumors of a xenograft mouse model. In tumor cells, miR-375 regulates CCL2 expression to increase recruitment of macrophages. Our study provides evidence for miR transfer from tumor cells to TAMs and identifies miR-375 as a crucial regulator of phagocyte infiltration and the subsequent development of a tumor-promoting microenvironment.

IntroductionPathogenic self-reactive antibody either in the form of soluble immune complexes or as a cellular-bound cytotoxic antibody produces fatal inflammatory responses in human autoimmune disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and hypersensitivity pneumonitis. Previous studies of immune complex-induced tissue injury in rodents have identified the roles of Fc receptors (FcRs) for immunoglobulin G (IgG; Fc␥Rs) and the complement anaphylatoxins (C3a and C5a) as well as their receptors (C3aR and C5aR). [1][2][3] By simultaneous triggering of activating and inhibitory signaling pathways, Fc␥Rs control a wide array of cellular responses, including phagocytosis, antibodydependent cell-mediated cytotoxicity, and release of inflammatory mediators, which ultimately can lead to cellular destruction and the amplification of normal and pathologic immune reactions in vivo. 4,5 In the mouse, there are 3 classes of activating Fc␥Rs: the highaffinity receptor Fc␥RI, the low-affinity receptor Fc␥RIII, and the recently described Fc␥RIV. 3,6 All these Fc␥Rs form heterooligomeric complexes with the same FcR ␥-chain (FcR␥), which contains an immunoreceptor tyrosine-based activation motif (ITAM) sequence that is required for cell activation. 1 IgG ligand crosslinking of FcR␥-associated Fc␥Rs on innate immune cells, such as macrophages, mast cells, natural killer cells, and neutrophils, results in tyrosine phosphorylation of the ITAM with subsequent recruitment of SH2-containing molecules and adaptor proteins that regulate the activation of effector enzymes, including phospholipase (PL) C␥ leading to production of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP 3 ) followed by influx of extracellular Ca 2ϩ into the cytosol. 3,[7][8][9][10] In immune cells, the predominant pathway of Ca 2ϩ entry is thought to involve IP 3 -receptor mediated Ca 2ϩ release from the endoplasmic reticulum (ER) Ca 2ϩ store, which in turn induces the opening of plasma membrane-expressed store-operated Ca 2ϩ (SOC) channels, also known as calcium release-activated Ca 2ϩ (CRAC) channels by a mechanism known as store-operated Ca 2ϩ entry (SOCE). 11,12 In addition, DAG and some of its metabolites have been shown to induce non-store-operated Ca 2ϩ entry (non-SOCE). 13 Although SOCE has long been recognized as a major pathway of Ca 2ϩ signaling, the principal proteins mediating this process have been discovered only recently. Stromal interaction molecule 1 (STIM1) is an ER-resident Ca 2ϩ sensor that connects ER store depletion to the activation of SOC/CRAC channels. [14][15][16][17] In its N terminus, STIM1 contains an "EF hand" that is located in the ER lumen and binds Ca 2ϩ with low affinity. After store depletion, STIM1 accumulates in regions of ER-plasma membrane appositions (puncta), which appear to be the sites of Ca 2ϩ entry. There it colocalizes with the 4-transmembrane domain protein Orai1 (also called CRACM1), 15,[18][19][20][21] which has b...

Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7−/−) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7−/− mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7−/− mice and in mice reconstituted with bone marrow cells from 5-HT7−/− mice compared with control mice after DSS colitis. 5-HT7−/− mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.