TY - JOUR
T1 - Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor Immunity
AU - Casazza, Andrea
AU - Laoui, Damya
AU - Wenes, Mathias
AU - Rizzolio, Sabrina
AU - Bassani, Nicklas
AU - Mambretti, Marco
AU - Deschoemaeker, Sofie
AU - VanGinderachter, JoA
AU - Tamagnone, Luca
AU - Mazzone, Massimiliano
PY - 2013/12/9
Y1 - 2013/12/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84891930215&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891930215&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.11.007
DO - 10.1016/j.ccr.2013.11.007
M3 - Article
C2 - 24332039
AN - SCOPUS:84891930215
VL - 24
SP - 695
EP - 709
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -