Background-Nitric oxide (NO) production is increased in postischemic myocardium, and NO can control mitochondrial oxygen consumption in vitro. Therefore, we investigated the role of endothelial NO synthase (eNOS)-derived NO on in vivo regulation of oxygen consumption in the postischemic heart. Methods and Results-Mice were subjected to 30 minutes of coronary ligation followed by 60 minutes of reperfusion.Myocardial oxygen tension (PO 2 ) was monitored by electron paramagnetic resonance oximetry. In wild-type, N-nitro-L-arginine methyl ester (L-NAME)-treated (with 1 mg/mL in drinking water), and eNOS knockout (eNOS Ϫ/Ϫ ) mice, no difference was observed among baseline myocardial PO 2 values (8.6Ϯ0.7, 10.0Ϯ1.2, and 10.1Ϯ1.2 mm Hg, respectively) or those measured at 30 minutes of ischemia (1.4Ϯ0.6, 2.3Ϯ0.9, and 3.1Ϯ1.4 mm Hg, respectively). After reperfusion, myocardial PO 2 increased markedly (PϽ0.001 versus baseline in each group) but was much lower in L-NAME-treated and eNOS Ϫ/Ϫ mice (17.4Ϯ1.6 and 20.4Ϯ1.9 mm Hg) than in wild-type mice (46.5Ϯ1.7 mm Hg; PϽ0.001). A transient peak of myocardial PO 2 was observed at early reperfusion in wild-type mice. No reactive hyperemia was observed during early reperfusion. Endothelial NO decreased the rate-pressure product (PϽ0.05), upregulated cytochrome c oxidase (CcO) mRNA expression (PϽ0.01) with no change in CcO activity, and inhibited NADH dehydrogenase (NADH-DH) activity (PϽ0.01) without alteration of NADH-DH mRNA expression. Peroxynitrite-mediated tyrosine nitration was higher in hearts from wild-type mice than in eNOS Ϫ/Ϫ or L-NAME-treated hearts. Conclusions-eNOS-derived

BackgroundColorectal cancer (CRC), which frequently metastasizes to the liver, is one of the three leading causes of cancer-related deaths worldwide. Growing evidence suggests that a subset of cells exists among cancer stem cells. This distinct subpopulation is thought to contribute to liver metastasis; however, it has not been fully explored in CRC yet.MethodsFlow cytometry analysis was performed to detect distinct subsets with CD133 and CXCR4 markers in human primary and metastatic CRC tissues. The 'stemness' and metastatic capacities of different subpopulations derived from the colon cancer cell line HCT116 were compared in vitro and in vivo. The roles of epithelial-mesenchymal transition (EMT) and stromal-cell derived factor-1 (SDF-1) in the metastatic process were also investigated. A survival curve was used to explore the correlation between the content of CD133+CXCR4+ cancer cells and patient survival.ResultsIn human specimens, the content of CD133+CXCR4+ cells was higher in liver metastases than in primary colorectal tumors. Clonogenic and tumorigenic cells were restricted to CD133+ cells in the HCT116 cell line, with CXCR4 expression having no impact on the 'stemness' properties. We found that CD133+CXCR4+ cancer cells had a high metastatic capacity in vitro and in vivo. Compared with CD133+CXCR4- cells, CD133+CXCR4+ cancer cells experienced EMT, which contributed partly to their metastatic phenotype. We then determined that SDF-1/CXCL12 treatment could further induce EMT in CD133+CXCR4+ cancer cells and enhance their invasive behavior, while this could not be observed in CD133+CXCR4- cancer cells. Blocking SDF-1/CXCR4 interaction with a CXCR4 antagonist, AMD3100 (1,10-[1,4-phenylenebis(methylene)]bis-1,4,8,11 -tetraazacyclotetradecane octahydrochloride), inhibited metastatic tumor growth in a mouse hepatic metastasis model. Finally, a high percentage of CD133+CXCR4+ cells in human primary CRC was associated with a reduced two-year survival rate.ConclusionsStrategies targeting the SDF-1/CXCR4 interaction may have important clinical applications in the suppression of colon cancer metastasis. Further investigations on how high expression of CXCR4 and EMT occur in this identified cancer stem cell subset are warranted to provide insights into our understanding of tumor biology.

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