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Cancer Cell. 2013 Dec 9;24(6):695-709. doi: 10.1016/j.ccr.2013.11.007.

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

Author information

1
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.
2
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.
3
Institute for Cancer Research at Candiolo, Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy.
4
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. Electronic address: massimiliano.mazzone@vib-kuleuven.be.

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 by Sema3A/Nrp1 signaling.

PMID:
24332039
DOI:
10.1016/j.ccr.2013.11.007
[Indexed for MEDLINE]
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