Histidine-rich glycoprotein uptake and turnover is mediated by mononuclear phagocytes

PLoS One. 2014 Sep 22;9(9):e107483. doi: 10.1371/journal.pone.0107483. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Fibrosarcoma / metabolism
  • Humans
  • Inflammation / metabolism*
  • Leukocyte Common Antigens / metabolism
  • Mice
  • Neovascularization, Pathologic / metabolism*
  • Phagocytes / metabolism*
  • Protein Binding
  • Proteins / metabolism*
  • Stromal Cells / metabolism
  • Tissue Distribution


  • Proteins
  • histidine-rich proteins
  • Leukocyte Common Antigens

Grants and funding

This work was supported by grants from the Swedish Cancer Foundation and the Knut and Alice Wallenberg Foundation to Lena Claesson-Welsh. Sònia Tugues was funded by a grant from the URPP “Translational cancer research” from the University of Zurich. Peter Åkerud was supported by the Uppsala-Örebro Regional Research Council. Satoshi Honjo was supported by a postdoctoral grant from Manpei Suzuki Diabetes Foundation and the Japan Society for Promotion of Science (JSPS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.