1. Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3.
- Author
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Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, Ben-Nun Y, Miller V, Rachman-Tzemah C, Timaner M, Mumblat Y, Ilan N, Loven D, Hershkovitz D, Satchi-Fainaro R, Blum G, Sleeman JP, Vlodavsky I, and Shaked Y
- Subjects
- Animals, Cathepsins metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Endothelial Cells drug effects, Endothelial Cells metabolism, Female, Glucuronidase metabolism, Humans, Lymphatic Vessels metabolism, Macrophages drug effects, Macrophages metabolism, Mice, Inbred BALB C, Neoplasm Metastasis, Phenotype, Up-Regulation drug effects, Vascular Endothelial Growth Factor C blood, Vascular Endothelial Growth Factor C metabolism, Lymphangiogenesis drug effects, Macrophages pathology, Paclitaxel pharmacology, Vascular Endothelial Growth Factor Receptor-3 metabolism
- 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., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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