Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3

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, Yuval Shaked*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1344-1356
Number of pages13
JournalCell Reports
Volume17
Issue number5
DOIs
StatePublished - 25 Oct 2016

Funding

FundersFunder number
FP-7 program
German Israel Foundation1204-253.13/2012
Israel Cancer Research Funds708/12
Israeli Society for Clinical Oncology and Radiation Therapy
Seventh Framework Programme260633
European Research Council
Israel Science Foundation490/12

    Keywords

    • VEGF-C
    • chemotherapy
    • host response
    • lymphangiogenesis
    • macrophages
    • metastatis

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