title: Histidine-rich glycoprotein uptake and turnover is mediated by mononuclear phagocytes.
abstract: Histidine-rich glycoprotein (HRG) is implicated in tumor growth and metastasis by regulation of angiogenesis and inflammation. HRG is produced by hepatocytes and carried to tissues via the circulation. We hypothesized that HRG's tissue distribution and turnover may be mediated by inflammatory cells. Biodistribution parameters were analyzed by injection of radiolabeled, bioactive HRG in the circulation of healthy and tumor-bearing mice. 125I-HRG was cleared rapidly from the blood and taken up in tissues of healthy and tumor-bearing mice, followed by degradation, to an increased extent in the tumor-bearing mice. Steady state levels of HRG in the circulation were unaffected by the tumor disease both in murine tumor models and in colorectal cancer (CRC) patients. Importantly, stromal pools of HRG, detected in human CRC microarrays, were associated with inflammatory cells. In agreement, microautoradiography identified 125I-HRG in blood vessels and on CD45-positive leukocytes in mouse tissues. Moreover, radiolabeled HRG bound in a specific, heparan sulfate-independent manner, to differentiated human monocytic U937 cells in vitro. Suppression of monocyte differentiation by systemic treatment of mice with anti-colony stimulating factor-1 neutralizing antibodies led to reduced blood clearance of radiolabeled HRG and to accumulation of endogenous HRG in the blood. Combined, our data show that mononuclear phagocytes have specific binding sites for HRG and that these cells are essential for uptake of HRG from blood and distribution of HRG in tissues. Thereby, we confirm and extend our previous report that inflammatory cells mediate the effect of HRG on tumor growth and metastatic spread.
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sònia
authors.initials: S
authors.lastname: Tugues
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Francis
authors.initials: F
authors.lastname: Roche
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Oriol
authors.initials: O
authors.lastname: Noguer
authors.affiliation: Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sujata
authors.initials: S
authors.lastname: Bhoi
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Narendra
authors.initials: N
authors.lastname: Padhan
authors.affiliation: Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Akerud
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Honjo
authors.affiliation: Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Ram Kumar
authors.initials: RK
authors.lastname: Selvaraju
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Dept of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Department of Radiology, Oncology and Radiation sciences, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010586:Phagocytes / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D014018:Tissue Distribution; D000099053:Histidine-Rich Glycoprotein
chemical_list: D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D017493:Leukocyte Common Antigens