title: HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF.
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.
authors.affiliation: Uppsala University, Department of Genetics and Pathology, Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Sònia
authors.initials: S
authors.lastname: Tugues
authors.forename: Damya
authors.initials: D
authors.lastname: Laoui
authors.forename: Irja
authors.initials: I
authors.lastname: Johansson
authors.forename: Cathy
authors.initials: C
authors.lastname: Coulon
authors.forename: Mario Leonardo
authors.initials: ML
authors.lastname: Squadrito
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Segura
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Li
authors.forename: Ellen
authors.initials: E
authors.lastname: Knevels
authors.forename: Sandra
authors.initials: S
authors.lastname: Costa
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.forename: Tom
authors.initials: T
authors.lastname: Dresselaer
authors.forename: Peter
authors.initials: P
authors.lastname: Åkerud
authors.forename: Maria
authors.initials: M
authors.lastname: De Mol
authors.forename: Henriikka
authors.initials: H
authors.lastname: Salomäki
authors.forename: Mia
authors.initials: M
authors.lastname: Phillipson
authors.forename: Sabine
authors.initials: S
authors.lastname: Wyns
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.forename: Ian
authors.initials: I
authors.lastname: Buysschaert
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002630:Chemotactic Factors / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009362:Neoplasm Metastasis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D000099053:Histidine-Rich Glycoprotein
chemical_list: D000906:Antibodies; D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D016207:Cytokines; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D004002:Clodronic Acid; D000072483:Placenta Growth Factor