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1.  Autocrine Effects of Tumor-Derived Complement 
Cell reports  2014;6(6):1085-1095.
We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications.
PMCID: PMC4084868  PMID: 24613353
3.  The Interaction between Factor H and Von Willebrand Factor 
PLoS ONE  2013;8(8):e73715.
Complement factor H (fH) is a plasma protein that regulates activation of the alternative pathway, and mutations in fH are associated with a rare form of thrombotic microangiopathy (TMA), known as atypical hemolytic uremic syndrome (aHUS). A more common TMA is thrombotic thrombocytopenic purpura, which is caused by the lack of normal ADAMTS-13-mediated cleavage of von Willebrand factor (VWF). We investigated whether fH interacts with VWF and affects cleavage of VWF. We found that factor H binds to VWF in plasma, to plasma-purified VWF, and to recombinant A1 and A2 domains of VWF as detected by co-immunoprecipitation (co-IP) and surface plasmon resonance assays. Factor H enhanced ADAMTS-13-mediated cleavage of recombinant VWF-A2 as determined by quantifying the cleavage products using Western-blotting, enhanced cleavage of a commercially available fragment of VWF-A2 (FRETS-VWF73) as determined by fluorometric assay, and enhanced cleavage of ultralarge (UL) VWF under flow conditions as determined by cleavage of VWF-platelet strings attached to histamine stimulated endothelial cells. Using recombinant full-length and truncated fH molecules, we found that the presence of the C-terminal half of fH molecule is important for binding to VWF-A2 and for enhancing cleavage of the A2 domain by ADAMTS-13. We conclude that factor H binds to VWF and may modulate cleavage of VWF by ADAMTS-13.
PMCID: PMC3753316  PMID: 23991205
4.  Reduced GVHD in C3-deficient mice is associated with the decrease of donor Th1/Th17 differentiation 
Graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is mediated by the activation of recipient dendritic cells (DCs) and subsequent proliferation of donor T cells. Recently complement system has been shown to modulate adaptive immunity through the interaction between the complement system and lymphocytes. Complement proteins participate in the activation of DCs, antigen presentation to T cells, and proliferation of T cells. Our studies with a murine model of bone marrow transplantation (BMT) demonstrate that complement system regulates alloimmune responses in GVHD. Mice deficient in the central component of the complement system (C3−/−) had significantly lower GVHD-related mortality and morbidity compared to the wild type (WT) recipient mice. The number of donor-derived T cells including IFNγ+, IL17+ and IL17+IFNγ+ subsets was decreased in secondary lymphoid organs of C3−/− recipients. Furthermore, there was a reduction of recipient CD8α+CD11c+ in lymphoid organs. We conclude C3 regulates Th1/17 differentiation in BMT, and define a novel function of the complement system in GVHD.
PMCID: PMC3437318  PMID: 22664751
5.  Paraneoplastic Thrombocytosis in Ovarian Cancer 
The New England Journal of Medicine  2012;366(7):610-618.
The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.
We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.
Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.
These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. (Funded by the National Cancer Institute and others.)
PMCID: PMC3296780  PMID: 22335738
6.  Platelets in pulmonary vascular physiology and pathology 
Pulmonary Circulation  2012;2(3):291-308.
Almost a trillion platelets pass through the pulmonary circulation every minute, yet little is known about how they support pulmonary physiology or contribute to the pathogenesis of lung diseases. When considering this conundrum, three questions jump out: Does platelet production in the lungs occur? Why does severe thrombocytopenia—which undercuts the principal physiological role of platelets to effect hemostasis—not lead to pulmonary hemorrhage? Why does atherothrombosis—which platelets initiate, maintain, and trigger is other critically important arterial beds—not develop in the pulmonary artery? The purpose of this review is to explore these and derivative questions by providing data within a conceptual framework that begins to organize a subject that is largely unassembled.
PMCID: PMC3487299  PMID: 23130099
cell signaling; hemostasis; platelets; thrombosis; vascular biology
7.  Hepcidin in anemia of chronic heart failure 
American journal of hematology  2011;86(1):107-109.
Anemia is a common finding among patients with chronic heart failure. Although co-morbidities, such as kidney failure, might contribute to the pathogenesis of anemia, many patients with heart failure do not have any other obvious etiology for their anemia. We investigated whether anemia in heart failure is associated with an elevation in hepcidin concentration.
We used time-of-flight mass spectrometry to measure hepcidin concentration in urine and serum samples of patients with heart failure and in control subjects. We found that the concentration of hepcidin was lower in urine samples of patients with heart failure compared to those of control subjects. Serum hepcidin was also reduced in heart failure but was not significantly lower than that in controls. There were no significant differences between hepcidin levels in patients with heart failure and anemia compared to patients with heart failure and normal hemoglobin. We concluded that hepcidin probably does not play a major role in pathogenesis of anemia in patients with chronic heart failure.
PMCID: PMC3076004  PMID: 21080339
Anemias; Cytokines; Iron
8.  Role of Factor Xa Inhibitors in Cancer-Associated Thrombosis: Any New Data? 
Advances in Hematology  2011;2011:196135.
The association between cancer and venous thromboembolism (VTE) has been well documented in the literature. Prevention and treatment of VTE in cancer patients is imperative. Typically, the mainstay regimen for VTE prevention and treatment has been anticoagulation therapy, unless contraindicated. This therapy consists of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), factor Xa inhibitor, or vitamin K antagonist (VKA). Current guidelines recommend LMWH over VKA for the treatment of VTE in cancer patients. Factor-specific anticoagulants have been proven safe and effective, and recently factor Xa inhibitors have emerged as a treatment alternative to heparins and VKA. Currently, three factor Xa inhibitors have been identified: fondaparinux (the only one approved so far by the US Food and Drug Administration), idraparinux (in clinical trials), and idrabiotaparinux (in clinical trials). This paper will examine the role of these agents, focusing on fondaparinux, for the prevention and treatment of VTE in cancer patients.
PMCID: PMC3195274  PMID: 22013445
9.  P‐selectin glycoprotein ligand‐1 VNTR polymorphisms and risk of thrombosis in the antiphospholipid syndrome 
Annals of the Rheumatic Diseases  2007;66(10):1378-1380.
Antiphospholipid antibodies (aPLA) have been shown to enhance thrombus formation by increasing the expression of adhesive receptors such as P‐selectin on endothelial cells. The P‐selectin counter‐receptor on leucocytes is P‐selectin glycoprotein ligand‐1 (PSGL‐1). We have previously described a variable number of tandem repeats (VNTR) polymorphism in the mucin‐like region of PSGL‐1, with three alleles: allele A, 16 repeats; allele B, 15 repeats; and allele C, 14 repeats.
We compared the PSGL‐1 VNTR allele and genotype frequencies in 90 patients with antiphospholipid syndrome (APS) with thrombosis, 39 patients with persistent aPLA positivity without thrombosis, and 203 healthy controls.
The frequency of the B allele was significantly higher in patients with APS with thrombosis compared with patients without thrombosis (p = 0.023). When we compared the groups by genotype frequencies, we found a markedly higher frequency of the AB genotype in patients with APS with thrombosis than in aPLA‐positive patients without thrombosis (38.9% vs 10.3%, p = 0.001) or in normal population (38.9% vs 22.2%, p<0.01).
We suggest that the VNTR polymorphism of PSGL‐1 is a significant determinant of thrombotic predisposition in patients with APS. Furthermore, risk appears to correlate best with the combination of alleles inherited rather than with the presence of any particular allele.
PMCID: PMC1994305  PMID: 17545190
antiphospholipid syndrome; P‐selectin; P‐selectin glycoprotein ligand‐1; PSGL‐1 VNTR polymorphism; thrombosis
10.  Abnormal platelet function in C3-deficient mice 
Background and Objectives
The complement system is a biochemical cascade composed of several plasma proteins that can interact with endothelial cells and blood cells, including platelets. In order to investigate the effect of the complement system on platelets, we studied platelet function in C3-deficient mice that lack complement activity.
Method and Results
Tail-cut bleeding time was prolonged and platelet aggregation in response to protease activated receptor-4 (PAR4) peptide was decreased in C3-deficient mice compared to wild-type littermates. Platelet aggregation in response to other agonists (ADP and collagen) was similar between C3-deficient mice and their normal littermates. Isolated platelets from wild-type mice aggregate less in C3-deficient plasma than in normal plasma and conversely, addition of plasma from wild-type mice or plasma-purified C3 improved aggregation of C3-deficient platelets. We also monitored formation of murine arteriole or venule thrombi in an intravital microscopy thrombosis model. We found that C3-deficient mice had a significantly delayed thrombotic response in arterioles compared to their wild-type littermates. Furthermore, thrombi in C3-deficient mice were less stable and embolized more frequently than those in wild-type mice.
Platelets of C3-deficient mice have subnormal function resulting in a prolonged tail-cut bleeding time and delayed thrombosis after vessel wall injury.
PMCID: PMC2867673  PMID: 19291167
platelet; complement system; thrombosis
11.  Anticomplement therapy 
Biologics : Targets & Therapy  2008;2(4):671-685.
The complement system is an important part of innate immunity; however, as with other parts of the immune system, the complement system can become pathologically activated and create or worsen disease. Anticomplement reagents have been studied for several years, but only recently have they emerged as a viable therapeutic tool. Here, we describe the role of the complement system in a wide array of diseases, as well as the use of anticomplement therapy as treatment for these diseases in animal models and in human clinical trials. Specifically, we will discuss the role of anticomplement therapy in paroxysmal nocturnal hemoglobinuria, glomerulonephritis, and heart disease, including coronary artery disease, myocardial infarction, and coronary revascularization procedures such as percutaneous coronary angioplasty and coronary artery bypass graft surgery.
PMCID: PMC2727911  PMID: 19707448
complement; paroxysmal nocturnal hemoglobinuria; glomerulonephritis; myocardial infarction; cardiopulmonary bypass
12.  Platelet activation leads to activation and propagation of the complement system 
Inflammation and thrombosis are two responses that are linked through a number of mechanisms, one of them being the complement system. Various proteins of the complement system interact specifically with platelets, which, in turn, activates them and promotes thrombosis. In this paper, we show that the converse is also true: activated platelets can activate the complement system. As assessed by flow cytometry and immunoblotting, C3 deposition increased on the platelet surface upon cell activation with different agonists. Activation of the complement system proceeded to its final stages, which was marked by the increased generation of the anaphylotoxin C3a and the C5b-9 complex. We identified P-selectin as a C3b-binding protein, and confirmed by surface plasmon resonance binding that these two proteins interact specifically with a dissociation constant of 1 μM. Using heterologous cells expressing P-selectin, we found that P-selectin alone is sufficient to activate the complement system, marked by increases in C3b deposition, C3a generation, and C5b-9 formation. In summary, we have found that platelets are capable of activating the complement system, and have identified P-selectin as a receptor for C3b capable of initiating complement activation. These findings point out an additional mechanism by which inflammation may localize to sites of vascular injury and thrombosis.
PMCID: PMC2213112  PMID: 15781579

Results 1-12 (12)