The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.

Objective-To assess the long term functional result after percutaneous mitral commissurotomy and identify the predictors of event-free survival following 10 years of experience. Design-Analysis of clinical, echocardiographic, and haemodynamic variables at baseline and after the procedure by univariate and multivariate analyses (Cox model). Setting-University hospital. Patients-532 consecutive patients receiving percutaneous mitral commissurotomy in the same institution. Results-The mean (SD) follow up was 3.8 (4.0) years. Survival at 3, 5, and 7.5 years was 94%, 91%, and 83%, respectively; event-free survival was 84%, 74%, and 52%. Mitral valve anatomy was identified as the strongest independent predictor of eventfree survival. Age, cardiothoracic ratio, mean pulmonary artery pressure, and mean echocardiographic mitral gradient after commissurotomy were also found to be independent predictors of long term functional result. Event-free survival was 92%, 84%, and 70% at 3, 5, and 7.5 years in patients with favourable anatomy (echo score = 1), 86%, 73%, and 34% in patients with intermediate anatomy (echo score = 2), and 45%, 25%, and 16% in patients with unfavourable anatomy (echo score = 3). In patients aged < 65 years, the event-free survival rate was 80%, 70%, and 45% at 3, 5, and 7.5 years v 52%, 38%, and 17% in patients aged > 65 years. Conclusions-The anatomical form of the mitral valve and the patient's age were the most powerful predictors of event-free survival. Patients with intermediate or unfavourable anatomy and those aged > 65 years have low 5 and 7.5 year event-free survival rates. This must be taken into account when discussing the indications for percutaneous mitral commissurotomy; immediate mitral valve replacement is a reasonable alternative to balloon mitral commissurotomy in patients with higher risk of functional deterioration after the procedure. (Heart 1998;80:359-364)

SummaryCarcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is an immunoglobulin-like cell surface co-receptor expressed on epithelial, hematopoietic and endothelial cells. CEACAM1 functions as an adhesion molecule, mainly binding to itself or other members of the CEA family. We and others have previously shown that CEACAM1 is crucial for in vivo vascular integrity during ischemic neo-vascularization. Here, we have deciphered the roles of CEACAM1 in normal and pathological vascularization. We have found that Ceacam1-/-mice exhibit a significant increase in basal vascular permeability related to increased basal Akt and endothelial nitric oxide synthase (eNOS) activation in primary murine lung endothelial cells (MLECs). Moreover, CEACAM1 deletion in MLECs inhibits VEGF-mediated nitric oxide (NO) production, consistent with defective VEGF-dependent in vivo permeability in Ceacam1-/-mice. In addition, Ceacam1-null mice exhibit increased permeability of tumor vasculature. Finally, we demonstrate that CEACAM1 is tyrosine-phosphorylated upon VEGF treatment in a SHP-1-and Src-dependent manner, and that the key residues of the long cytoplasmic domain of CEACAM1 are crucial for CEACAM1 phosphorylation and NO production. This data represents the first report, to our knowledge, of a functional link between CEACAM1 and the VEGFR2/Akt/eNOS-mediated vascular permeability pathway.

We have shown that carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L) expression in MC38 metastatic colorectal cancer (CRC) cells results in liver metastasis inhibition via CCL2 and STAT3 signaling. But other molecular mechanisms orchestrating CEACAM1-L-mediated metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced ephrin type-A receptor 2 (EPHA2) expression and activity. An EPHA2-specific inhibitor reduced EPHA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high CEACAM1 in combination with low EPHA2 expression benefited from longer time to first recurrence/metastasis compared to those with high EPHA2 expression. With the added interaction of CEACAM6, we denoted that CEACAM1 high-and EPHA2 low-expressing patient samples with lower CEACAM6 expression also exhibited a longer time to first recurrence/metastasis. In HT29 human CRC cells, down-regulation of CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver metastasis through cell context-dependent EPHA2-mediated signaling. However, CEACAM1's role should be considered in the presence of other CEACAM family members. www.impactjournals.com/oncotarget/

Obesity enhances BC extravasation by modifying the endothelium. To investigate the effects of obesity on cancer extravasation, we used a syngeneic BC cell line derived from the C57BL6 mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model combined with a diet-induced obesity (DIO) model. Wild type (WT) C57BL6 female mice were enrolled on a low-fat (LF) (10% kcal) or high-fat (HF) (60% kcal) diet for 15 weeks (Fig. 1a,b) 10 , followed by tail vein injection of fluorescently labeled BC cells