Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3
Summary - 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...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 25, 2016
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| In: |
Cell reports
Year: 2016, Volume: 17, Issue: 5, Pages: 1344-1356 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2016.09.083 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.celrep.2016.09.083 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124716313560 
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| Author Notes: | Dror Alishekevitz, Svetlana Gingis-Velitski, Orit Kaidar-Person, Lilach Gutter-Kapon, Sandra D. Scherer, Ziv Raviv, Emmanuelle Merquiol, Yael Ben-Nun, Valeria Miller, Chen Rachman-Tzemah, Michael Timaner, Yelena Mumblat, Neta Ilan, David Loven, Dov Hershkovitz, Ronit Satchi-Fainaro, Galia Blum, Jonathan P. Sleeman, Israel Vlodavsky, and Yuval Shaked |
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| 520 | |a Summary - 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. | ||
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