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

Dror Alishekevitz | Zendy; Svetlana GingisVelitski | Zendy; Orit KaidarPerson | Zendy; Lilach Gutter-Kapon | Zendy; Sandra D. Scherer | Zendy; Ziv Raviv | Zendy; Emmanuelle Merquiol | Zendy; Yael BenNun | Zendy; Valeria Miller | Zendy; Chen Rachman-Tzemah | Zendy; Michael Timaner | Zendy; Yelena Mumblat | Zendy; Neta Ilan | Zendy; David Loven | Zendy; Dov Hershkovitz | Zendy; Ronit SatchiFainaro | Zendy; Galia Blum | Zendy; Jonathan P. Sleeman | Zendy; Israël Vlodavsky | Zendy; Yuval Shaked | Zendy

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

Author(s) -

Dror Alishekevitz,

Svetlana GingisVelitski,

Orit KaidarPerson,

Lilach Gutter-Kapon,

Sandra D. Scherer,

Ziv Raviv,

Emmanuelle Merquiol,

Yael BenNun,

Valeria Miller,

Chen Rachman-Tzemah,

Michael Timaner,

Yelena Mumblat,

Neta Ilan,

David Loven,

Dov Hershkovitz,

Ronit SatchiFainaro,

Galia Blum,

Jonathan P. Sleeman,

Israël Vlodavsky,

Yuval Shaked

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.09.083

Subject(s) - lymphangiogenesis , chemotherapy , cancer research , paclitaxel , heparanase , lymphatic system , metastasis , medicine , macrophage , downregulation and upregulation , vascular endothelial growth factor c , vascular endothelial growth factor , cancer , pathology , biology , vascular endothelial growth factor a , vegf receptors , in vitro , biochemistry , gene

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.

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