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

Citation:

Dror Alishekevitz, 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 , Sleeman, Jonathan P, Vlodavsky, Israel , ו Shaked, Yuval . 2016. “Macrophage-Induced Lymphangiogenesis And Metastasis Following Paclitaxel Chemotherapy Is Regulated By Vegfr3.”. Cell Reports, 17, 5, Pp. 1344–1356. doi:10.1016/j.celrep.2016.09.083.

תקציר:

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.