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      Histidine-rich glycoprotein (HRGP): Pleiotropic and paradoxical effects on macrophage, tumor microenvironment, angiogenesis, and other physiological and pathological processes


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          Histidine-rich glycoprotein (HRGP) is a relatively less known glycoprotein, but it is abundant in plasma with a multidomain structure, which allows it to interact with many ligands and regulate various biological processes. HRGP ligands includes heme, Zn 2+, thrombospondin, plasmin/plasminogen, heparin/heparan sulfate, fibrinogen, tropomyosin, IgG, FcγR, C1q. In many conditions, the histidine-rich region of HRGP strengthens ligand binding following interaction with Zn 2+ or exposure to low pH, such as sites of tissue injury or tumor growth. The multidomain structure and diverse ligand binding attributes of HRGP indicates that it can act as an extracellular adaptor protein, connecting with different ligands, especially on cell surfaces. Also, HRGP can selectively target IgG, which blocks the production of soluble immune complexes. The most common cell surface ligand of HRGP is heparan sulfate proteoglycan, and the interaction is also potentiated by elevated Zn 2+ concentration and low pH. Recent reports have shown that HRGP can modulate macrophage polarization and possibly regulate other physiological processes such as angiogenesis, anti-tumor immune response, fibrinolysis and coagulation, soluble immune complex clearance and phagocytosis of apoptotic/necrosis cells. In addition, it has also been reported that HRGP has antibacterial and anti-HIV infection effects and may be used as a novel clinical biomarker accordingly. This review outlines the molecular, structural and biological properties of HRGP as well as presenting an update on the function of HRGP in various physiological processes.

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          Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.

          Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
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            Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.

            Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. The widely held view is that these antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Here, I review emerging evidence supporting an alternative hypothesis-that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. Drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if both are carefully scheduled. A better understanding of the molecular and cellular underpinnings of vascular normalization may ultimately lead to more effective therapies not only for cancer but also for diseases with abnormal vasculature, as well as regenerative medicine, in which the goal is to create and maintain a functionally normal vasculature.
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              Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes.

              Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6C(hi)CX(3)CR1(low) monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally "re-educating" the TAM compartment. (c)2010 AACR.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                08 August 2020
                March 2022
                08 August 2020
                : 9
                : 2
                : 381-392
                [1]Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200120, PR China
                Author notes
                []Corresponding author. hekang929@ 123456163.com
                [∗∗ ]Corresponding author. xiaqiang@ 123456shsmu.edu.cn
                © 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 24 April 2020
                : 15 July 2020
                : 31 July 2020
                Review Article

                angiogenesis,histidine-rich glycoprotein,macrophage polarization,thrombospondin,tumor


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