title: Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization.
abstract: Histidine-rich glycoprotein (HRG) is a 75-kDa heparin-binding plasma protein implicated in the regulation of tumor growth and vascularization. In this study, we show that hrg(-/-) mice challenged with fibrosarcoma or pancreatic carcinoma grow larger tumors with increased metastatic properties. Compared with wild-type mice, fibrosarcomas in hrg(-/-) mice were more hypoxic, necrotic, and less perfused, indicating enhanced vessel abnormalization. HRG deficiency was associated with a suppressed antitumor immune response, with both increased infiltration of M2 marker-expressing macrophages and decreased infiltration of dendritic cells and cytotoxic T cells. Analysis of transcript expression in tumor-associated as well as peritoneal macrophages from hrg(-/-) mice revealed an increased expression of genes associated with a proangiogenic and immunoinhibitory phenotype. In accordance, expression arrays conducted on HRG-treated peritoneal macrophages showed induction of genes involved in extracellular matrix biology and immune responsiveness. In conclusion, our findings show that macrophages are a direct target of HRG. HRG loss influences macrophage gene regulation, leading to excessive stimulation of tumor angiogenesis, suppression of tumor immune response, and increased tumor growth and metastatic spread.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sònia
authors.initials: S
authors.lastname: Tugues
authors.forename: Satoshi
authors.initials: S
authors.lastname: Honjo
authors.forename: Christian
authors.initials: C
authors.lastname: König
authors.forename: Oriol
authors.initials: O
authors.lastname: Noguer
authors.forename: Marie
authors.initials: M
authors.lastname: Hedlund
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.forename: Sofie
authors.initials: S
authors.lastname: Deschoemaeker
authors.forename: Mathias
authors.initials: M
authors.lastname: Wenes
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: D000818:Animals; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology; D000099053:Histidine-Rich Glycoprotein
chemical_list: D011506:Proteins; D000099053:Histidine-Rich Glycoprotein