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.
Bibliographical noteFunding Information:
This study was supported by research grants from the European Research Council (under the FP-7 program, 260633 ), the Israel Science Foundation ( 490/12 ), and Israel Cancer Research Funds ( 708/12 ) (Y.S.). This study was also supported by research grants from the German Israel Foundation ( 1204-253.13/2012 ) (Y.S. and J.P.S.) and the Israeli Society for Clinical Oncology and Radiation Therapy (O.K.-P. and Y.S.).
© 2016 The Author(s)
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