HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF

Cancer Cell. 2011 Jan 18;19(1):31-44. doi: 10.1016/j.ccr.2010.11.009. Epub 2011 Jan 6.

Abstract

Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HRG relies substantially on downregulation of placental growth factor (PlGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PlGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemotactic Factors / metabolism
  • Clodronic Acid / pharmacology
  • Culture Media, Conditioned / pharmacology
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Down-Regulation / genetics*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / drug effects
  • Microvessels / pathology
  • Microvessels / ultrastructure
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / pathology
  • Neoplasms / blood supply
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / immunology*
  • Neovascularization, Pathologic / pathology
  • Placenta Growth Factor
  • Pregnancy Proteins / genetics
  • Pregnancy Proteins / immunology
  • Pregnancy Proteins / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proteins / pharmacology
  • Regional Blood Flow / drug effects
  • Regional Blood Flow / genetics
  • Transfection

Substances

  • Antibodies
  • Chemotactic Factors
  • Culture Media, Conditioned
  • Cytokines
  • PGF protein, human
  • Pgf protein, mouse
  • Pregnancy Proteins
  • Proteins
  • histidine-rich proteins
  • Clodronic Acid
  • Placenta Growth Factor