Targeting of the NOX1/ADAM17 Enzymatic Complex Regulates Soluble MCAM-Dependent Pro-Tumorigenic Activity in Colorectal Cancer.

The melanoma cell adhesion molecule, shed from endothelial and cancer cells, is a soluble growth factor that induces tumor angiogenesis and growth. However, the molecular mechanism accounting for its generation in a tumor context is still unclear. To investigate this mechanism, we performed in vitro experiments with endothelial/cancer cells, gene expression analyses on datasets from human colorectal tumor samples, and applied pharmacological methods in vitro/in vivo with mouse and human colorectal cancer cells.

Targeting OLFML3 in Colorectal Cancer Suppresses Tumor Growth and Angiogenesis, and Increases the Efficacy of Anti-PD1 Based Immunotherapy.

The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers.

Deletion of the clock gene Period2 (Per2) in glial cells alters mood-related behavior in mice.

The circadian clock regulates many biochemical and physiological pathways, and lack of clock genes, such as Period (Per) 2, affects not only circadian activity rhythms, but can also modulate feeding and mood-related behaviors. However, it is not known how cell-type specific expression of Per2 contributes to these behaviors. In this study, we find that Per2 in glial cells is important for balancing mood-related behaviors, without affecting circadian activity parameters.

MAGI1 localizes to mature focal adhesion and modulates endothelial cell adhesion, migration and angiogenesis.

MAGI1 is an intracellular adaptor protein that stabilizes cell junctions and regulates epithelial and endothelial integrity. Here, we report that that in endothelial cells MAGI1 colocalizes with paxillin, β3-integrin, talin 1, tensin 3 and α-4-actinin at mature focal adhesions and actin stress fibers, and regulates their dynamics. Downregulation of MAGI1 reduces focal adhesion formation and maturation, cell spreading, actin stress fiber formation and RhoA/Rac1 activation.

Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis-Contribution of New Antibodies for Therapy.

The fundamental role of cell adhesion molecules in mediating various biological processes as angiogenesis has been well-documented. CD146, an adhesion molecule of the immunoglobulin superfamily, and its soluble form, constitute major players in both physiological and pathological angiogenesis. A growing body of evidence shows soluble CD146 to be significantly elevated in the serum or interstitial fluid of patients with pathologies related to deregulated angiogenesis, as autoimmune diseases, obstetric and ocular pathologies, and cancers.

Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in CD146-positive invasive tumors.

Initially discovered in human melanoma, CD146/MCAM is expressed on many tumors and is correlated with cancer progression and metastasis. However, targeting CD146 remains challenging since it is also expressed on other cell types, as vessel cells, where it displays important physiological functions. We previously demonstrated that CD146 is shed as a soluble form (sCD146) that vectorizes the effects of membrane CD146 on tumor angiogenesis, growth and survival.

Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy.

NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771.

MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress.

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress.

Stem cell properties of peripheral blood endothelial progenitors are stimulated by soluble CD146 via miR-21: potential use in autologous cell therapy.

Cell-based therapies constitute a real hope for the treatment of ischaemic diseases. One of the sources of endothelial progenitors for autologous cell therapy is Endothelial Colony Forming Cells (ECFC) that can be isolated from peripheral blood. However, their use is limited by their low number in the bloodstream and the loss of their stem cell phenotype associated with the acquisition of a senescent phenotype in culture.

Consensus guidelines for the use and interpretation of angiogenesis assays.

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations.

Junctional adhesion molecule C (JAM-C) dimerization aids cancer cell migration and metastasis.

Most cancer deaths result from metastasis, which is the dissemination of cells from a primary tumor to distant organs. Metastasis involves changes to molecules that are essential for tumor cell adhesion to the extracellular matrix and to endothelial cells. Junctional Adhesion Molecule C (JAM-C) localizes at intercellular junctions as homodimers or more affine heterodimers with JAM-B.

A novel anti-CD146 antibody specifically targets cancer cells by internalizing the molecule.

CD146 is an adhesion molecule present on many tumors (melanoma, kidney, pancreas, breast, ...

Therapeutic and Diagnostic Antibodies to CD146: Thirty Years of Research on Its Potential for Detection and Treatment of Tumors.

CD146 (MCAM, MUC18, S-Endo1) is a transmembrane glycoprotein belonging to both CAM and mucin families. It exists as different splice variants and is cleaved from the membrane by metalloproteases to generate a soluble form. CD146 is expressed by numerous cancer cells as well as being one of the numerous proteins expressed by the vascular endothelium.

Erythropoietin Pretreatment of Transplanted Endothelial Colony-Forming Cells Enhances Recovery in a Cerebral Ischemia Model by Increasing Their Homing Ability: A SPECT/CT Study.

Unlabelled: Endothelial colony-forming cells (ECFCs) are promising candidates for cell therapy of ischemic diseases, as less than 10% of patients with an ischemic stroke are eligible for thrombolysis. We previously reported that erythropoietin priming of ECFCs increased their in vitro and in vivo angiogenic properties in mice with hindlimb ischemia. The present study used SPECT/CT to evaluate whether priming of ECFCs with erythropoietin could enhance their homing to the ischemic site after transient middle cerebral artery occlusion (MCAO) followed by reperfusion in rats and potentiate their protective or regenerative effect on blood-brain barrier (BBB) disruption, cerebral apoptosis, and cerebral blood flow (CBF).

ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors' Angiogenic Potential and Homing Ability.

Background: Alternate erythropoietin (EPO)-mediated signaling via the EPOR/CD131 heteromeric receptor exerts the tissue-protective actions of EPO in a wide spectrum of injuries, especially ischemic diseases. Circulating endothelial progenitor cells contribute to endothelial repair and post-natal angiogenesis after chronic ischemic injury. This work aims to investigate the effects of ARA290, a specific agonist of EPOR/CD131 complex, on a subpopulation of endothelial progenitor cells named endothelial colony-forming cells (ECFCs) and to characterize its contribution to ECFCs-induced angiogenesis after peripheral ischemia.

Soluble CD146 boosts therapeutic effect of endothelial progenitors through proteolytic processing of short CD146 isoform.

Aims: Endothelial colony-forming cells (ECFC) constitute an endothelial progenitor fraction with a promising interest for the treatment of ischaemic cardiovascular diseases. As soluble CD146 (sCD146) is a new factor promoting angiogenesis, we examined whether sCD146 priming could improve the therapeutic potential of ECFC and defined the involved mechanism.

Methods And Results: We investigated the effects of sCD146 priming on regenerative properties of ECFC in vivo.

Soluble melanoma cell adhesion molecule (sMCAM/sCD146) promotes angiogenic effects on endothelial progenitor cells through angiomotin.

The melanoma cell adhesion molecule (CD146) contains a circulating proteolytic variant (sCD146), which is involved in inflammation and angiogenesis. Its circulating level is modulated in different pathologies, but its intracellular transduction pathways are still largely unknown. Using peptide pulldown and mass spectrometry, we identified angiomotin as a sCD146-associated protein in endothelial progenitor cells (EPC).

Identification of soluble CD146 as a regulator of trophoblast migration: potential role in placental vascular development.

Both vasculogenesis and angiogenesis occur during normal placental vascular development. Additionally, the placenta undergoes a process of vascular mimicry (pseudo-vasculogenesis) where the placental extravillous trophoblast (EVT) that invade the spiral arteries convert from an epithelial to an endothelial phenotype during normal pregnancy. As soluble CD146 (sCD146) constitutes a new physiological factor with angiogenic properties, we hypothesized that it could be involved in the regulation of placental vascular development by acting on EVT.

Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase.

Proprotein convertases (PCs) are a family of serine proteases that are involved in the post-translational processing and activation of a wide range of regulatory proteins. The upstream role of PCs in the control of many physiological and pathological processes generates a growing interest in understanding their regulation. Here, we demonstrate that the serine protease inhibitor plasminogen activator inhibitor 1 (PAI-1) forms an SDS-stable complex with the PC furin, which leads to the inhibition of the intra-Golgi activity of furin.