2.1. CD146 Expression Pattern and Functions

CD146 is expressed all along the vascular tree regardless of the vessel size and anatomical location, including endothelial cells, smooth muscle cells, and pericytes ^[23]. This distribution pattern is important for maintaining vessel architecture through heterotypic interaction among these cells via CD146 and its binding partners. As mentioned earlier, the long and the short membrane isoforms have different localizations on endothelial cells. lgCD146 is mainly stored intracellularly when the cells are not confluent. However, at confluency, lgCD146 is redistributed to inter-cellular junctions, outside the tight or adherens junctions, and regulate cell–cell cohesion, paracellular permeability, and monocyte transmigration. shCD146 is involved in regulating endothelial cells adhesion, migration, proliferation, and consequently angiogenesis ^[21]. CD146 was first identified on melanoma cells as a poor prognostic marker correlating with disease progression, but was later found to be expressed on various cancer cell lines such as breast, kidney, gastric, ovarian, and prostate cancers [14,20,24]^[14][20][24]. The mechanisms underlying CD146 upregulation on cancer cells remain to be found. Elevated membrane CD146 expression and high soluble CD146 concentration in plasma are associated with increased cancer cell proliferation, motility, metastatic dissemination, and tumor angiogenesis, along with a decrease in patients’ overall survival ^[25]. Moreover, CD146 is also expressed on several immune cell subsets, in particular on T lymphocytes [26,27]^[26][27]. Along this line, it was demonstrated that soluble factors in the tumor microenvironment induce CD146 expression on tumor infiltrating T lymphocytes. Indeed, the density of CD146 expressed on tumor-infiltrating CD4+ T cells is higher than that on peripheral T cells [26,28]^[26][28]. Analysis of the RNA profile of CD4+ CD146+ T cells from peripheral blood shows high levels of genes associated with Th17 cells (IL-17A, ROR-γ, IL-22, IL-26, IL-23R, CXCL-13, IL1-β, GM-CSF) which exacerbate inflammatory reactions and indirectly promote tumor progression ^[27]. In addition, Th17 cells contribute to auto-immune diseases progression as in multiple sclerosis (MS) and systemic sclerosis (SS). In fact, CD146+Th17 cells constitute the principal T-cell subset in the cerebrospinal fluid of MS patients and is considered as a poor prognostic marker ^[29]. CD146 was also found to be expressed on the intermediate and extra-villous trophoblasts [30,31]^[30][31].

2.2. CD146 Ligands and Signaling

Initially considered as an orphan receptor, successive studies have identified new ligands for CD146 (Table 1). Most of the newly discovered ligands emphasize the role of CD146 in angiogenesis, as these ligands were found to promote angiogenic effects on endothelial cells. For example, in one study, authors showed that netrin-1, a neuronal guidance molecule, induces human umbilical vein endothelial cells (HUVEC) proliferation, migration, and tube formation by interacting with CD146 but not VEGFR2 ^[32]. They also showed that netrin-1 binds to the domain IV of CD146 to induce activation of P38 and Erk1/2, a characteristic signaling pathway implicated in VEGFR2 signaling, and relied this effect to the fact that CD146 also acts as a co-receptor for VEGFR2. Indeed, siRNA experiments targeting CD146 abolished the angiogenic effects of netrin-1 on HUVECs while the knock-down of VEGFR2 barely induced similar results. In the same study, the authors used a monoclonal anti-CD146 antibody, AA98, which blocks CD146. They showed that netrin-1 lost its angiogenic effects after treating HUVECs with AA98. Consistently, AA98 efficiently reduced the number of blood vessels in Matrigel plugs conditioned with netrin-1 and grafted in mice, when compared to the group treated with netrin-1 without the antibody. Likewise, in a zebrafish embryo model, antisense morpholino oligonucleotides (MO) targeting CD146 inhibited netrin-1-induced angiogenesis and blocked the development of parachordal vessels. These data underscore the relevance of CD146 as a potent angiogenic molecule both in vitro and in vivo and highlight the capability of CD146 to mediate angiogenic signals even in the absence of conventional pro-angiogenic molecules like VEGF or b-FGF.

Galectins are a family of soluble carbohydrate-binding lectins that mediate cell-to-cell and cell-to-ECM adhesions. As glycosylation accounts for nearly 35% of CD146 apparent molecular weight, it was tempting to speculate that CD146 could interact with sugar-binding proteins such as lectins. In particular, galectin-1, a protein produced by vascular, interstitial, epithelial, and immune cells, was found to interact readily with N-linked oligosaccharides of membrane CD146 and signal to protect endothelial cells from apoptosis as well as to regulate angiogenesis ^[33]. In this study, Jouve et al. evidenced that CD146 is mainly N-glycosylated and validated its interaction with galectin-1. They showed that galectin-1, by binding CD146, was protecting endothelial cells from apoptosis. In addition, in vivo experiments in zebrafish showed impaired vascular network formation and poorly developed intersomitic vessels upon knocking down galectin-1 ^[34] and CD146 ^[16], respectively. Moreover, in a galectin-1 knockout (KO) mouse model ^[34], tumor growth was markedly impaired and this effect was attributed to a weak tumor angiogenesis. In the same way, administration of anti-CD146 monoclonal antibody AA98 potently reduced tumor vessel formation in nude mice xenografted with human tumor cells (SMMC7721, SK-LMS-1, SW1990). Another study by Thijssen et al. ^[35] has shown that galectin-1 is significantly upregulated on activated endothelium and positively correlates with strong angiogenesis by augmenting VEGF receptors and transforming protein p21 (GTPase H-RAS) signaling and phosphorylation. Thus, galectin-1 effect on angiogenesis could be, at least in part, mediated by CD146, which is indeed a coreceptor for VEGFR2. Importantly, it was recently described that endothelial CD146 binds platelet-derived growth factor receptor-β (PDGFR-β) on pericyte and regulates the PDGF-induced activation of PDGFR-β signaling ^[36]. By this mechanism, CD146 appears to have a crucial role in recruiting adjacent pericytes in the endothelium, and hence, stabilize the developing vessels. All other ligands that are documented in the literature to interact directly with CD146 are summarized in Table 1 along with the consequent biological significance.

Concerning sCD146, its binding partners are still largely unknown. In fact, angiomotin was described to be among the first binding partners of sCD146 on endothelial cells. Stalin et al. ^[22] showed that the interaction between sCD146 and angiomotin on endothelial cells induces cell proliferation, migration, and pseudo-capillary formation in Matrigel. This interaction activates angiogenesis and exerts a competitive inhibitory effect on angiostatin. Recently, integrin αvβ1 has been reported to interact with sCD146, an interaction that appears to be important in regulating blood brain barrier (BBB) permeability ^[37].

2.3. CD146 Mechanism of Action

CD146 is mainly a monomeric protein. However, it has been shown to dimerize and multimerize in response to physiological stimuli [46]^[38]. Indeed, the stimulation of endothelial cells with VEGF or by means of anti-CD146 AA98 antibody results in CD146 dimerization as revealed by fluorescence resonance energy transfer (FRET) technology. This dimerization leads to conformational changes in CD146 structure and induces changes in ligand binding. However, whether this dimerization causes receptor auto-activation and -phosphorylation is not elucidated yet.

CD146 can interact with diverse ligands that mediate and alter endothelial functions (Figure 1). In fact, CD146 activation induces the phosphorylation of p125^FAK and paxillin along with p59^fyn recruitment in cultured endothelial cells, leading to actin cytoskeleton reorganization and activation of transcription factors that modulate cell migration and survival [47]^[39]. Moreover, the intracellular domain of CD146 interacts physically with actin linked proteins of the ezrin-radixin-moesin (ERM) family, bringing them to the level of membrane protrusions. This CD146-mediated formation of microvilli like extensions will then allow the activation of RhoA by sequestering Rho guanine nucleotide dissociation inhibitory factor 1 (RhoGDI1), leading to an increase in cell motility. In addition, the stimulation of melanoma cells with Wnt5a induces CD146 redistribution within polarized structures known as W-RAMP (Wnt5a-mediated receptor-actin-myosin polarity), leading to membrane retraction and cell migration in a RhoA-mediated mechanism [48]^[40]. Finally, a defect in CD146 expression is associated with an upregulation of the canonical Wnt pathway and a downregulation of the non-canonical pathway [49]^[41].

Figure 1. Schematic representation of CD146 cellular localization and regulation.(MEIS1: myeloid ecotropic viral integration site 1; HIF1-α: hypoxia-inducible factor 1 alpha; TGF-β: transforming growth factor-beta; IFN-γ: interferon-gamma; BMP-4: bone morphogenetic protein 4; ox-LDL: oxidized low density lipoprotein; ZBTB7A: zinc finger and BTB domain-containing protein 7A; FAK: focal adhesion kinase; BAD: Bcl-2 associated agonist of cell death; ERM: ezrin, radixin, and moesin; PLC-γ: phospholipase C-gamma).

On endothelial cells, both VEGFR2 and CD146 extracellular domains were found to interact physically even without VEGF binding ^[11]. A study showed that CD146 dimerizes upon VEGF-A stimulation in a mechanism involving RAC1, Nox4, and ROS production [50]^[42]. The inhibition of CD146 using siRNAs, miRNAs, or inhibitory antibodies as AA98 decreased VEGF-A-induced VEGFR2, p38/MAPK, and AKT phosphorylation and reduced NFκB activation in HUVECs ^[11]. Similarly, in lung vascular endothelial cells from CD146KO mice, VEGF-A stimulation resulted in decreased VEGFR2 and FAK phosphorylation [51]^[43]. Additionally, by regulating further junctional proteins such as VE-cadherin and PECAM, CD146 mediates VEGF-induced permeability in endothelial cells.

As mentioned earlier, CD146 can interact with netrin-1 and mediate angiogenesis ^[32]. It has been shown in zebrafish that CD146 silencing inhibits netrin-1-induced vascularization. However, netrin-1 does not always stimulate angiogenesis. The controversy about its angiogenic role is attributed to the binding partner, as netrin-1 preferentially binds CD146 at low concentrations but UNC5B at high concentrations. Indeed, netrin-1 has higher affinity for CD146 as compared to its cognate ligand UNC5B. By binding UNC5B, signals will be triggered to counteract those of CD146 and thus inhibit angiogenesis ^[32]. On the other hand, netrin-1 can induce CD146 dimerization and VEGFR2 phosphorylation, and the inhibition of CD146 decreases netrin-1 effect on HUVEC migration, proliferation, and tube formation in vitro by reducing VEGFR2, ERK1/2, and p38 activation.

Soluble CD146 is also involved in activating several signaling pathways. Stalin et al. showed that soluble CD146 binds angiomotin P80 on endothelial progenitor cells and HUVECs and regulates vessel formation and cell migration ^[22]. Mechanistically, soluble CD146 triggers a signalosome constituted of angiomotin, short CD146, VEGFR1, VEGFR2, and presenilin-1 in lipid rafts and phosphorylates VEGF receptors 1 and 2 on endothelial cells [52]^[44]. Within this signalosome, soluble CD146 promotes the proteolytic cleavage of short CD146 extracellular domain through matrix metalloproteinases/a disintegrin and metalloproteinase (MMP/ADAM), followed by intracellular cleavage of the cytoplasmic domain by presenilin-1. The generated so-called short CD146 intracellular fragment (shCD146 IC) will be then translocated to the nucleus where it associates with the transcription factor CSL to regulate the transcription of FADD, Bcl-xl, and eNOS genes that are involved in cell survival and angiogenesis [52]^[44].

Soluble CD146 also significantly contributes to tumor progression in different manners. This form, by associating with its cognate binding partners on cancer cells, activates the oncogene c-myc, which in turn activates signaling pathways leading to increased cell proliferation and migration ^[13].

Reference  (we'll rearrange the references after you submitted it)

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