The tumor necrosis factor (TNF) and TNF receptor superfamilies (TNFSF and TNFRSF) consist of approximately 50 membrane and soluble proteins that can modulate cellular function. Most of these molecules are expressed by or can target cells of the immune system, and they have a wide range of actions including promoting cellular differentiation, survival, and production of inflammatory cytokines and chemokines. Emerging data show that TNFSF ligand–receptor signaling pathways are active in inflammatory and autoimmune disease. Furthermore, several genetic polymorphisms in TNFSF and TNFRSF associate with susceptibility to developing disease. Here, we examine recent data regarding the potential of these molecules as targets for therapy of autoimmune and inflammatory disease.

Agonistic anti–4-1BB suppresses autoimmune and allergic inflammation via binding to Galectin-9, which facilitates 4-1BB aggregation, signaling, and functional activity.

Plexin-A4 activity is essential for Toll-like receptor–induced signaling, cytokine production, and inflammation in mice.

IntroductionExtracellular nucleotides are released and detectable in a high concentration within the tumor microenvironment. G protein-coupled P2Y2 nucleotide receptor (P2Y2R) is activated equipotently by adenosine triphosphate (ATP) and uridine 5′-triphosphate (UTP), which mediate proinflammatory responses such as cell migration and proliferation. However, the role of P2Y2R in the process of cancer metastasis remains unclear. This study aimed to determine the role of P2Y2R in the proliferation, migration and invasion of highly metastatic MDA-MB-231 breast cancer cells through crosstalk with endothelial cells (ECs).MethodsATP release and P2Y2R activity between high metastatic breast cancer cell MDA-MB-231 and low metastatic breast cancer cell MCF-7 were compared. Then, the role of P2Y2R on tumor growth and invasion via crosstalk with ECs was examined in vitro, using MDA-MB-231 cells and ECs transfected with control- or P2Y2R-siRNA, and in vivo, using an animal model injected with control-shRNA- or P2Y2R-shRNA-transfected MDA-MB-231 cells.ResultsWe found that this highly metastatic breast cancer cell line released higher levels of ATP and showed a higher P2Y2R activity in comparison to a low metastatic breast cancer cell line, MCF-7. In MDA-MB-231 cells, P2Y2R activation by ATP or UTP increased proliferation at 24 or 72 hours, which was abolished by P2Y2R knock-down. In addition, the adhesion of MDA-MB-231 cells to ECs and cell migration were both significantly increased by ATP or UTP through the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in MDA-MB-231 or ECs but not in cells where P2Y2R was knocked down. Furthermore, ATP- or UTP-mediated activation of P2Y2R induced MDA-MB-231 invasion through ECs, increased matrix metalloproteinase-9 (MMP-9) activity and vascular endothelial growth factor (VEGF) production in MDA-MB-231 and induced the phosphorylation of vascular endothelial (VE)-cadherin in ECs. Tumor growth and metastasis to other tissues were dramatically reduced, and body weight was increased in mice injected with P2Y2R-shRNA-transfected MDA-MB-231 cells compared to mice injected with control shRNA-transfected MDA-MB-231 cells.ConclusionThis study suggests that P2Y2R may play an important role in cancer metastasis via modulation of the crosstalk between cancer cells and ECs.Electronic supplementary materialThe online version of this article (doi:10.1186/bcr3694) contains supplementary material, which is available to authorized users.

Morin, a flavonoid found in figs and other Moraceae, displays a variety of biological actions, such as anti-oxidant, anti-inflammatory and anti-carcinogenic. However, the anticancer effects of morin and in particular its anti-metastatic effects are not well known. Therefore, in the present study, we investigated the anticancer effects of morin on highly metastatic human breast cancer cells. Our results showed that morin significantly inhibited the colony forming ability of highly metastatic MDA-MB‑231 breast cancer cells from low doses (50 µM) without cytotoxicity. In addition, morin changed MDA-MB‑231 cell morphology from mesenchymal shape to epithelial shape and inhibited the invasion of MDA-MB‑231 cells in a dose-dependent manner. Morin decreased matrix metalloproteinase-9 (MMP-9) secretion and expression of the mesenchymal marker N-cadherin of MDA-MB‑231 cells, suggesting that morin might suppress the EMT process. Furthermore, morin significantly decreased the phosphorylation of Akt, and inhibition of the Akt pathway significantly reduced MDA-MB‑231 invasion. In an in vivo xenograft mouse model, morin suppressed MDA-MB‑231 cancer cell progression. Taken together, our findings suggest that morin exhibits an inhibitory effect on the cancer progression and EMT process of highly metastatic breast cancer cells at least in part through inhibiting Akt activation. This study provides evidence that morin may have anticancer effects against metastatic breast cancer.