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Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity

Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M.

Cancer Cell. 2013 Dec 9;24(6):695-709.

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium and

Laboratory of Myeloid Cell Immunology, VIB, 1050 Brussels, Belgium; Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, 1050 Brussels, Belgium and

Institute for Cancer Research at Candiolo, Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy and

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology andAngiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium. Electronic address: [email protected]

 

Abstract

 

Recruitment of tumor-associated macrophages (TAMs) into avascular areas sustains tumor progression; however, the underlying guidance mechanisms are unknown. Here, we report that hypoxia-induced Semaphorin 3A (Sema3A) acts as an attractant for TAMs by triggering vascular endothelial growth factor receptor 1 phosphorylation through the associated holoreceptor, composed of Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4. Importantly, whereas Nrp1 levels are downregulated in the hypoxic environment, Sema3A continues to regulate TAMs in an Nrp1-independent manner by eliciting PlexinA1/PlexinA4-mediated stop signals, which retain them inside the hypoxic niche. Consistently, gene deletion of Nrp1 in macrophages favors TAMs’ entrapment in normoxic tumor regions, which abates their pro-angiogenic and immunosuppressive functions, hence inhibiting tumor growth and metastasis. This study shows that TAMs’ heterogeneity depends on their localization, which is tightly controlled bySema3A/Nrp1 signaling.

 

Copyright © 2013 Elsevier Inc. All rights reserved.

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