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. © 2011 Elsevier Inc.

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

Mazzone M.;Li X.;De Palma M.;
2011-01-01

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. © 2011 Elsevier Inc.
2011
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1
31
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Animals; Antibodies; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Chemotactic Factors; Clodronic Acid; Culture Media, Conditioned; Cytokines; Dendritic Cells; Down-Regulation; Endothelial Cells; Gene Expression; Humans; Hypoxia; Lung Neoplasms; Macrophages; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microvessels; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Placenta Growth Factor; Pregnancy Proteins; Proteins; Regional Blood Flow; Transfection
Rolny C.; Mazzone M.; Tugues S.; Laoui D.; Johansson I.; Coulon C.; Squadrito M.L.; Segura I.; Li X.; Knevels E.; Costa S.; Vinckier S.; Dresselaer T.; Akerud P.; De Mol M.; Salomaki H.; Phillipson M.; Wyns S.; Larsson E.; Buysschaert I.; Botling J.; Himmelreich U.; Van Ginderachter J.A.; De Palma M.; Dewerchin M.; Claesson-Welsh L.; Carmeliet P.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1841509
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