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

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.
AuthorsAndrea Casazza, Damya Laoui, Mathias Wenes, Sabrina Rizzolio, Nicklas Bassani, Marco Mambretti, Sofie Deschoemaeker, Jo A Van Ginderachter, Luca Tamagnone, Massimiliano Mazzone
JournalCancer cell (Cancer Cell) Vol. 24 Issue 6 Pg. 695-709 (Dec 09 2013) ISSN: 1878-3686 [Electronic] United States
PMID24332039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Sema3a protein, mouse
  • Semaphorin-3A
  • Neuropilin-1
Topics
  • Animals
  • Cell Hypoxia
  • Macrophages (drug effects, physiology)
  • Mice
  • Mice, Knockout
  • Neoplasms, Experimental (blood supply, immunology, pathology)
  • Neovascularization, Pathologic (prevention & control)
  • Neuropilin-1 (antagonists & inhibitors, genetics, physiology)
  • Semaphorin-3A (antagonists & inhibitors, physiology)
  • Signal Transduction (physiology)

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