Histidine-Rich Glycoprotein Can Prevent Development of Mouse Experimental Glioblastoma

Abstract

Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).

Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics

“…These proteins are highly specific to GBM irrespective of their location in brain, thus providing important insights into the disease pathology as has been demonstrated by the validated proteins and their involvement in various events of tumorigenesis. Our analysis also provided several other upregulated proteins, like SERPH, PDIA1, CERU, TENA, VTNC, APOE, LEG1, HRG, and FKBP5, that are known to be involved in tumor progression, aggressiveness, and invasion in GBM (3,17,18,28,30,32,39,45,47). In addition to known GBM-associated proteins, novel potential biomarkers identified in this study include CLIC4, NP1L1, IGKC, TAGL2, and YES (Supplementary Table S1).…”

Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma

“…50 In contrast, whether HRG plays a predominately proangiogenic or antiangiogenic role in vivo under normal and pathologic conditions remains uncertain because conflicting results have been reported with the use of a variety of mouse models. 17,[46][47][48][49] Furthermore, because most HRG functions have been proposed on the basis of in vitro observations in which purified native/ recombinant protein, protein fragments, or synthetic peptides are used, it is imperative to validate whether HRG is truly a multifunctional protein in both immunity and vascular biology using HRG Ϫ/Ϫ mice ( Table 1). Of importance, whether HRG simply functions as a regulator or is a key molecule in either a nonredundant or redundant pathway remains to be determined.…”

“…Indeed, recent in vivo studies in which the authors used a number of murine tumor models have demonstrated the ability of HRG to inhibit the growth and vascularization of fibrosarcoma tumors, 47 as well as the development of malignant glioma (Table 1). 49 Furthermore, HRG Ϫ/Ϫ mice were shown to exhibit enhanced tumor angiogenesis when the Rip1-Tag2 pancreatic tumor model was used, indicating that endogenous HRG can function as an antiangogenic factor. 48 Contrary to these findings, studies by Klenotic et al 17 demonstrated that the expression of HRG by glioma cells in both subcutaneous and orthotopic brain tumor models resulted in an increase in tumor size and angiogenesis, possibly by blocking the antiangiogenic activity of vasculostatin (Table 1).…”

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

“…12 for a review). Tumor angiogenesis is inhibited by HRG and peptides derived from its central His/Pro-rich domain, leading to reduced vascularization and growth of different syngeneic tumor models (13)(14)(15)(16). HRG inhibits adhesion and chemotaxis of primary endothelial cells in vitro (17), providing a mechanism for the effect of HRG in attenuation of tumor angiogenesis.…”