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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. 1; 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 1; Vlodavsky, Israel; ... mehr

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.

Volltext §
DOI: 10.5445/IR/1000061422
DOI: 10.1016/j.celrep.2016.09.083
Zitationen: 70
Web of Science
Zitationen: 69
Zitationen: 79
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2016
Sprache Englisch
Identifikator ISSN: 2211-1247
KITopen-ID: 1000061422
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in Cell reports
Verlag Cell Press
Band 17
Heft 5
Seiten 1344 - 1356
Vorab online veröffentlicht am 25.10.2016
Schlagwörter lymphangiogenesis, chemotherapy, host response, macrophages, metastatis, VEGF-C
Nachgewiesen in Dimensions
Web of Science
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