Summary Platelet microparticles (PMP) are endogenous substances generated during the coagulation process in a hypercoagulable state. This study demonstrated that PMP promote the proliferation and survival, migration, and tube formation in human umbilical vein endothelial cells (HUVEC). Heat‐treated PMP did not significantly decrease the angiogenic activity in HUVEC compared with that of the untreated PMP. Meanwhile when PMP were treated with activated charcoal, a procedure known to remove the lipid growth factors, the angiogenic activity was significantly reduced. These results suggest that the lipid component(s) of the PMP may be major active factor(s) and that protein component(s) may be minor contributor(s). PMP were also shown to augment endothelial progenitor cell differentiation in peripheral blood mononuclear cells. In addition, PMP‐stimulated proliferation, chemotaxis and tube formation of the HUVEC was mediated via the Pertussis toxin‐sensitive G protein, extracellular signal‐regulated kinase and the phosphoinositide 3‐kinase pathway. Herein, a new action of PMP was demonstrated to be a potent angiogenic stimulator. It is expected that in pathological states such as a growing tumour, PMP shed from the circulating platelets may reach adequate concentrations and that the elevated levels of PMP could contribute to florid formation of new blood vessels.
Exosomes are endosome derived extracellular vesicles of 30–120 nm size ranges. Exosomes have been identified as mediators of cell-to-cell communication by transferring bioactive molecules such as nucleic acids, proteins and lipids into recipient cells. While exosomes are secreted by multiple cell types, cancer derived exosomes not only influence the invasive potentials of proximally located cells, but also affect distantly located tissues. Based on their ability to alter tumor microenvironment by regulating immunity, angiogenesis and metastasis, there has been growing interest in defining the clinical relevance of exosomes in cancers. In particular, exosomes are valuable sources for biomarkers due to selective cargo loading and resemblance to their parental cells. In this review, we summarize the recent findings to utilize exosomes as cancer biomarkers for early detection, diagnosis and therapy selection.
Integrin-associated protein (IAP)1 is important in host defense where it is required for integrin-dependent functions of polymorphonuclear leukocytes (1). IAP also appears to be important in modulating integrin function in other cells (2) and in signal transduction upon ligand binding by certain integrins with which it associates (3, 4). We have recently discovered that IAP is a receptor for the COOH-terminal cell binding domain (CBD) of the thrombospondins (TSs) including TS1 (5), the most abundant protein of platelet ␣ granules (6). A peptide from the CBD, kRFYVVMWKk (4N1K) has been identified as an IAP agonist (2, 5). TS1 is thought to have a role in augmenting platelet aggregation (7,8). A mAb (C6.7) against the IAPbinding domain of TS1 can block secretion-dependent platelet aggregation (8), but the mechanism of this effect has remained obscure (9). IAP is present on platelets (10), but it was initially reported to have no functional role in platelet activation or aggregation (11). However, Dorahy et al. (12) have recently reported that the 4N1K agonist peptide, which we had identified in the CBD of TS1, can activate washed platelets causing their aggregation. In nucleated cells, IAP associates with ␣v3 and modulates its function (3, 4). For example, the CBD of TS1 and the 4N1K peptide stimulate the chemotaxis of endothelial cells on RGD-containing substrata, and this effect is blocked specifically by mAbs against IAP and ␣v3 (5). TS1, its CBD, and 4N1K peptide all stimulate the rapid spreading of C32 melanoma and NIH3T3 cells on sparse vitronectin substrata, which support only weak, slow spreading of these cells in the absence of TS1 (2). This stimulation of ␣v3-dependent spreading is specifically inhibited by pertussis toxin, indicating the participation of a heterotrimeric G i -like protein in a pathway linking IAP to a common cellular pathway resulting in protein kinase C activation, which leads to cell spreading (2) and motility (5). This sort of stimulation of an integrin-dependent function via G protein-dependent pathways is reminiscent of the costimulation of ␣IIb3 function in platelets by agents that act via heptahelical or seven transmembrane spanning receptors such as ADP, epinephrine, and thrombin (13, 14). Here we have examined the hypothesis that IAP ligation by TS1 has a role in modulating ␣IIb3 function. We find that IAP stimulation by its agonist 4N1K activates ␣IIb3 as judged by enhanced binding of the conformationally sensitive mAb PAC-1 (13-15) resulting in spreading of platelets on fibrinogen-coated surfaces, aggregation of stirred platelets (12), and assembly of a signaling complex containing IAP, the integrin, c-Src, FAK, and SYK. All of these actions of IAP are blocked by pertussis toxin, indicating the essential participation of a G i -like heterotrimeric G protein (2). In unstirred, washed platelets where the integrin is not engaged, 4N1K stimulates the tyrosine phosphorylation of SYK, an early event in platelet activation by many agonists (17). This activation of SYK is bloc...
Integrin-associated protein (CD47) is a multiply membrane spanning member of the immunoglobulin superfamily that regulates some adhesion-dependent cell functions through formation of a complex with αvβ3 integrin and trimeric G proteins. Cholesterol is critical for the association of the three protein components of the supramolecular complex and for its signaling. The multiply membrane spanning domain of IAP is required for complex formation because it binds cholesterol. The supramolecular complex forms preferentially in glycosphingolipid-enriched membrane domains. Binding of mAb 10G2 to the IAP Ig domain, previously shown to be required for association with αvβ3, is affected by both the multiply membrane spanning domain and cholesterol. These data demonstrate that cholesterol is an essential component of the αvβ3/IAP/G protein signaling complex, presumably acting through an effect on IAP conformation.
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