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

Alishekevitz, Dror; Gingis-Velitski, Svetlana; Kaidar-Person, Orit; Gutter-Kapon, Lilach; Scherer, Sandra D.; Raviv, Ziv; Merquiol, Emmanuelle; Ben-Nun, Yael; Miller, Valeria; Rachman-Tzemah, Chen; Timaner, Michael; Mumblat, Yelena; Ilan, Neta; Loven, David; Hershkovitz, Dov; Satchi-Fainaro, Ronit; Blum, Galia; P. Sleeman, Jonathan; Vlodavsky, Israel; Shaked, Yuval

Abstract (englisch):
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.


Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Jahr 2016
Sprache Englisch
Identifikator DOI: 10.1016/j.celrep.2016.09.083
ISSN: 2211-1247
URN: urn:nbn:de:swb:90-614223
KITopen ID: 1000061422
HGF-Programm 47.01.01; LK 01
Erschienen in Cell reports
Band 17
Heft 5
Seiten 1344 - 1356
Schlagworte lymphangiogenesis, chemotherapy, host response, macrophages, metastatis, VEGF-C
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