TY - JOUR
T1 - Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3
AU - Alishekevitz, Dror
AU - Gingis-Velitski, Svetlana
AU - Kaidar-Person, Orit
AU - Gutter-Kapon, Lilach
AU - Scherer, Sandra D.
AU - Raviv, Ziv
AU - Merquiol, Emmanuelle
AU - Ben-Nun, Yael
AU - Miller, Valeria
AU - Rachman-Tzemah, Chen
AU - Timaner, Michael
AU - Mumblat, Yelena
AU - Ilan, Neta
AU - Loven, David
AU - Hershkovitz, Dov
AU - Satchi-Fainaro, Ronit
AU - Blum, Galia
AU - P. Sleeman, Jonathan
AU - Vlodavsky, Israel
AU - Shaked, Yuval
N1 - Publisher Copyright:
© 2016 The Author(s)
PY - 2016/10/25
Y1 - 2016/10/25
N2 - While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice.
AB - While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice.
KW - chemotherapy
KW - host response
KW - lymphangiogenesis
KW - macrophages
KW - metastatis
KW - VEGF-C
UR - https://www.scopus.com/pages/publications/84994759902
U2 - 10.1016/j.celrep.2016.09.083
DO - 10.1016/j.celrep.2016.09.083
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C2 - 27783948
AN - SCOPUS:84994759902
SN - 2211-1247
VL - 17
SP - 1344
EP - 1356
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -
