Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein

Thulin, Åsa; Ringvall, Maria; Dimberg, Anna; Kårehed, Karin; Väisänen, Timo; Väisänen, Marja-Riitta; Hamad, Osama A.; Wang, Jian; Bjerkvig, Rolf; Nilsson, Bo; Pihlajaniemi, Taina; Åkerud, Helena; Pietras, Kristian; Jahnen-Dechent, Willi; Siegbahn, Agneta; Olsson, Anna‐Karin

doi:10.1158/1541-7786.mcr-09-0094

Cited by 41 publications

(75 citation statements)

References 40 publications

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“…Our data extend a recent report on enhanced tumor growth but unaffected angiogenesis in established pancreatic tumors in HRG-deficient Rip1-Tag2 mice (40), which were sensitive to treatment with a platelet-depleting antibody. HRG negatively affected the angiogenic switch as shown by the increased incidence of hemoglobin-containing pancreatic islets in the absence of HRG in the RipTag2 model (41). The potential contribution of platelets to the immunomodulatory role of HRG remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

Genetic Deficiency in Plasma Protein HRG Enhances Tumor Growth and Metastasis by Exacerbating Immune Escape and Vessel Abnormalization

et al. 2012

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Histidine-rich glycoprotein (HRG) is a 75-kDa heparin-binding plasma protein implicated in the regulation of tumor growth and vascularization. In this study, we show that hrg À/À mice challenged with fibrosarcoma or pancreatic carcinoma grow larger tumors with increased metastatic properties. Compared with wild-type mice, fibrosarcomas in hrg À/À mice were more hypoxic, necrotic, and less perfused, indicating enhanced vessel abnormalization. HRG deficiency was associated with a suppressed antitumor immune response, with both increased infiltration of M2 marker-expressing macrophages and decreased infiltration of dendritic cells and cytotoxic T cells. Analysis of transcript expression in tumor-associated as well as peritoneal macrophages from hrg À/À mice revealed an increased expression of genes associated with a proangiogenic and immunoinhibitory phenotype. In accordance, expression arrays conducted on HRG-treated peritoneal macrophages showed induction of genes involved in extracellular matrix biology and immune responsiveness. In conclusion, our findings show that macrophages are a direct target of HRG. HRG loss influences macrophage gene regulation, leading to excessive stimulation of tumor angiogenesis, suppression of tumor immune response, and increased tumor growth and metastatic spread. Cancer Res; 72(8); 1953-63. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Genetic Deficiency in Plasma Protein HRG Enhances Tumor Growth and Metastasis by Exacerbating Immune Escape and Vessel Abnormalization

et al. 2012

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“…28 A peptide corresponding to the HRR/ PRR fragment has been identified in human tissue samples but the mechanism by which the interdomain disulfide is reduced is not known. 29 Using x-ray crystallography we present the first structural characterization of HRG. We reveal that the N2 domain of serum-purified rabbit HRG does indeed possess a cystatin-like fold and is N-glycosylated at Asn184.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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Key Points• The x-ray crystal structure of the N2 domain from HRG at 1.93Å resolution is presented.• The structure reveals an S-glutathionyl adduct at Cys185, which has implications for angiogenic regulation.Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that flank a histidine-rich region (HRR), and a C-terminal domain. To date, structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93Å resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain, forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a 5-stranded antiparallel b-sheet wrapped around a 5-turn a-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the antiangiogenic cleavage product from HRG. (Blood. 2014;123(12):1948-1955 Introduction Histidine-rich glycoprotein (HRG) is a plasma protein that regulates angiogenesis, coagulation, and immune function in vertebrates. Human HRG has an approximate mass of 70 kDa and is present in plasma at low micromolar concentrations (ca ;1.5 mM). The protein is arranged into 6 domains: 2 N-terminal domains (N1 and N2), a central histidine-rich region (HRR) flanked by 2 proline rich regions (PRR1 and PRR2), and a C-terminal domain (C). The N1, N2, and C domains are highly conserved between species, as is an arrangement of 6 disulfide bridges (Figure 1). In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate.1-9 HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets. 11HRG is heavily glycosylated; the human protein has 6 putative N-linked glycosylation sites.11 The histidine-and proline-rich regions are predicted to be intrinsically disordered but N1, N2, and the C-terminal domains are likely to have ordered structures. The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors.12 Type 1 cystatins (also known as stefins) are characterized b...

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“…In addition to release and generation, a third mechanism to locally increase the concentration of an angiogenesis inhibitor during platelet activation has been described. This mechanism involves creation of a microenvironment that favors retention of the anti-angiogenic molecule at sites of platelet degranulation (Thulin et al, 2009). This finding may reflect a host response to counteract angiogenesis during pathological conditions where platelets are activated.…”

Section: The Role Of Platelets In Tumor Angiogenesis and Growthmentioning

confidence: 99%

“…Moreover, mice lacking the endogenous angiogenesis inhibitor histidine-rich glycoprotein (HRG) have a coagulation defect and enhanced activation of platelets (Tsuchida-Straeten et al, 2005;Ringvall et al, 2011). HRG-deficient Rip1-Tag2 mice, a transgenic model of insulinoma, have a significantly increased number of angiogenic islets of Langerhans in their pancreas (Thulin et al, 2009). This elevated angiogenic switch can be suppressed by induction of thrombocytopenia, i.e.…”

Section: The Role Of Platelets In Tumor Angiogenesis and Growthmentioning

confidence: 99%

Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis

Cedervall¹,

Olsson²

2012

Tumor Angiogenesis

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Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein

Abstract: The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine-and proline-rich (His/Pro-rich) domain.

Cited by 41 publications

References 40 publications

Genetic Deficiency in Plasma Protein HRG Enhances Tumor Growth and Metastasis by Exacerbating Immune Escape and Vessel Abnormalization

Genetic Deficiency in Plasma Protein HRG Enhances Tumor Growth and Metastasis by Exacerbating Immune Escape and Vessel Abnormalization

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis

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