HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF |
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| Authors: | Rolny Charlotte Mazzone Massimiliano Tugues Sònia Laoui Damya Johansson Irja Coulon Cathy Squadrito Mario Leonardo Segura Inmaculada Li Xiujuan Knevels Ellen Costa Sandra Vinckier Stefan Dresselaer Tom Åkerud Peter De Mol Maria Salomäki Henriikka Phillipson Mia Wyns Sabine Larsson Erik Buysschaert Ian Botling Johan Himmelreich Uwe Van Ginderachter Jo A De Palma Michele Dewerchin Mieke Claesson-Welsh Lena Carmeliet Peter |
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| Institution: | Uppsala University, Department of Genetics and Pathology, Rudbeck Laboratory, 75185 Uppsala, Sweden. |
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| 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. |
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