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.
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Authors | Andrea Casazza, Damya Laoui, Mathias Wenes, Sabrina Rizzolio, Nicklas Bassani, Marco Mambretti, Sofie Deschoemaeker, Jo A Van Ginderachter, Luca Tamagnone, Massimiliano Mazzone |
Journal | Cancer cell
(Cancer Cell)
Vol. 24
Issue 6
Pg. 695-709
(Dec 09 2013)
ISSN: 1878-3686 [Electronic] United States |
PMID | 24332039
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier Inc. All rights reserved. |
Chemical References |
- Sema3a protein, mouse
- Semaphorin-3A
- Neuropilin-1
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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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