title: Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3.
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.
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Dror
authors: D
authors: Alishekevitz
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Svetlana
authors: S
authors: Gingis-Velitski
authors: Division of Oncology, Rambam Health Care Campus, 3109601 Haifa, Israel.
authors: Orit
authors: O
authors: Kaidar-Person
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Lilach
authors: L
authors: Gutter-Kapon
authors: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany; Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
authors: Sandra D
authors: SD
authors: Scherer
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Ziv
authors: Z
authors: Raviv
authors: The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel.
authors: Emmanuelle
authors: E
authors: Merquiol
authors: The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel.
authors: Yael
authors: Y
authors: Ben-Nun
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Valeria
authors: V
authors: Miller
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Chen
authors: C
authors: Rachman-Tzemah
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Michael
authors: M
authors: Timaner
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Yelena
authors: Y
authors: Mumblat
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Neta
authors: N
authors: Ilan
authors: Department of Oncology, Ha'Emek Medical Center, 1834111 Afula, Israel.
authors: David
authors: D
authors: Loven
authors: Department of Pathology, Rambam Health Care Campus, 3109601 Haifa, Israel.
authors: Dov
authors: D
authors: Hershkovitz
authors: Department of Pharmacology, Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel.
authors: Ronit
authors: R
authors: Satchi-Fainaro
authors: The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel.
authors: Galia
authors: G
authors: Blum
authors: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany; Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
authors: Jonathan P
authors: JP
authors: Sleeman
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
authors: Israel
authors: I
authors: Vlodavsky
authors: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel. Electronic address: yshaked@tx.technion.ac.il.
authors: Yuval
authors: Y
authors: Shaked
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D015854:Up-Regulation / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000097:blood / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D002403:Cathepsins; D005966:Glucuronidase; D017239:Paclitaxel; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D000099175:Heparanase
keywords: VEGF-C; chemotherapy; host response; lymphangiogenesis; macrophages; metastatis