The role of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer

The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology

Protein phosphatase 2A improves cardiac functional response to ischemia and sepsis

Reversible protein phosphorylation is a posttranslational modification of regulatory proteins involved in cardiac signaling pathways. Here, we focus on the role of protein phosphatase 2A (PP2A) for cardiac gene expression and stress response using a transgenic mouse model with cardiac myocyte-specific overexpression of the catalytic subunit of PP2A (PP2A-TG). Gene and protein expression were assessed under basal conditions by gene chip analysis and Western blotting. Some cardiac genes related to the cell metabolism and to protein phosphorylation such as kinases and phosphatases were altered in PP2A-TG compared to wild type mice (WT). As cardiac stressors, a lipopolysaccharide (LPS)-induced sepsis in vivo and a global cardiac ischemia in vitro (stop-flow isolated perfused heart model) were examined. Whereas the basal cardiac function was reduced in PP2A-TG as studied by echocardiography or as studied in the isolated work-performing heart, the acute LPS- or ischemia-induced cardiac dysfunction deteriorated less in PP2A-TG compared to WT. From the data, we conclude that increased PP2A activity may influence the acute stress tolerance of cardiac myocytes

Bone marrow-independent adventitial macrophage progenitor cells contribute to angiogenesis

Pathological angiogenesis promotes tumor growth, metastasis, and atherosclerotic plaque rupture. Macrophages are key players in these processes. However, whether these macrophages differentiate from bone marrow-derived monocytes or from local vascular wall-resident stem and progenitor cells (VW-SCs) is an unresolved issue of angiogenesis. To answer this question, we analyzed vascular sprouting and alterations in aortic cell populations in mouse aortic ring assays (ARA). ARA culture leads to the generation of large numbers of macrophages, especially within the aortic adventitia. Using immunohistochemical fate-mapping and genetic in vivo-labeling approaches we show that 60% of these macrophages differentiate from bone marrow-independent Ly6c$^{+}$/Sca-1$^{+}$ adventitial progenitor cells. Analysis of the NCX$^{−/-}$ mouse model that genetically lacks embryonic circulation and yolk sac perfusion indicates that at least some of those progenitor cells arise yolk sac-independent. Macrophages represent the main source of VEGF in ARA that vice versa promotes the generation of additional macrophages thereby creating a pro-angiogenetic feedforward loop. Additionally, macrophage-derived VEGF activates CD34$^{+}$ progenitor cells within the adventitial vasculogenic zone to differentiate into CD31$^{+}$ endothelial cells. Consequently, depletion of macrophages and VEGFR2 antagonism drastically reduce vascular sprouting activity in ARA. In summary, we show that angiogenic activation induces differentiation of macrophages from bone marrow-derived as well as from bone marrow-independent VW-SCs. The latter ones are at least partially yolk sac-independent, too. Those VW-SC-derived macrophages critically contribute to angiogenesis, making them an attractive target to interfere with pathological angiogenesis in cancer and atherosclerosis as well as with regenerative angiogenesis in ischemic cardiovascular disorders

Aging‐related carcinoembryonic antigen‐related cell adhesion molecule 1 signaling promotes vascular dysfunction

Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF‐α is CEACAM1‐dependently upregulated in the aging vasculature. Vice versa, TNF‐α induces CEACAM1 expression. This results in a feed‐forward loop in the aging vasculature that maintains a chronic pro‐inflammatory milieu. Furthermore, we demonstrate that age‐associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age‐dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR‐2 signaling. Consequently, aging‐related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis

Regulation of the endothelin system by shear stress in human endothelial cells

In this study, the effect of shear stress on the expression of genes of the human endothelin-1 system was examined. Primary cultures of human umbilical vein endothelial cells (HUVEC) were exposed to laminar shear stress of 1, 15 or 30 dyn cm−2 (i.e. 0.1, 1.5 or 3 N m−2) (venous and two different arterial levels of shear stress) in a cone-and-plate viscometer.Laminar shear stress transiently upregulates preproendothelin-1 (ppET-1) mRNA, reaching its maximum after 30 min (approx 1.7-fold increase). In contrast, long-term application of shear stress (24 h) causes downregulation of ppET-1 mRNA in a dose-dependent manner.Arterial levels of shear stress result in downregulation of endothelin-converting enzyme-1 isoform ECE-1a (predominating in HUVEC) to 36.2 ± 8.5%, and isoform ECE-1b mRNA to 72.3 ± 1.9% of static control level.The endothelin-1 (ET-1) release is downregulated by laminar shear stress in a dose-dependent manner.This downregulation of ppET-1 mRNA and ET-1 release is not affected by inhibition of protein kinase C (PKC), or tyrosine kinase. Inhibition of endothelial NO synthase (L-NAME, 500 μm) prevents downregulation of ppET-1 mRNA by shear stress.In contrast, increasing degrees of long-term shear stress upregulate endothelin receptor type B (ETB) mRNA by a NO- and PKC-, but not tyrosine kinase-dependent mechanism.In conclusion, our data suggest the downregulation of human endothelin synthesis, and an upregulation of the ETB receptor by long-term arterial laminar shear stress. These effects might contribute to the vasoprotective and anti-arteriosclerotic potential of arterial laminar shear stress