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

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

doi:10.1016/j.celrep.2016.09.083

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

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

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

85 Scopus citations

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.

Original language	American English
Pages (from-to)	1344-1356
Number of pages	13
Journal	Cell Reports
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2016.09.083
State	Published - 25 Oct 2016

Bibliographical note

Funding Information:
This study was supported by research grants from the European Research Council (under the FP-7 program, 260633 ), the Israel Science Foundation ( 490/12 ), and Israel Cancer Research Funds ( 708/12 ) (Y.S.). This study was also supported by research grants from the German Israel Foundation ( 1204-253.13/2012 ) (Y.S. and J.P.S.) and the Israeli Society for Clinical Oncology and Radiation Therapy (O.K.-P. and Y.S.).

Publisher Copyright:
© 2016 The Author(s)

Keywords

VEGF-C
chemotherapy
host response
lymphangiogenesis
macrophages
metastatis

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10.1016/j.celrep.2016.09.083

Cite this

Alishekevitz, D., Gingis-Velitski, S., Kaidar-Person, O., Gutter-Kapon, L., Scherer, S. D., Raviv, Z., Merquiol, E., Ben-Nun, Y., Miller, V., Rachman-Tzemah, C., Timaner, M., Mumblat, Y., Ilan, N., Loven, D., Hershkovitz, D., Satchi-Fainaro, R., Blum, G., P. Sleeman, J., Vlodavsky, I., & Shaked, Y. (2016). Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3. Cell Reports, 17(5), 1344-1356. https://doi.org/10.1016/j.celrep.2016.09.083

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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.",

keywords = "VEGF-C, chemotherapy, host response, lymphangiogenesis, macrophages, metastatis",

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

note = "Funding Information: This study was supported by research grants from the European Research Council (under the FP-7 program, 260633 ), the Israel Science Foundation ( 490/12 ), and Israel Cancer Research Funds ( 708/12 ) (Y.S.). This study was also supported by research grants from the German Israel Foundation ( 1204-253.13/2012 ) (Y.S. and J.P.S.) and the Israeli Society for Clinical Oncology and Radiation Therapy (O.K.-P. and Y.S.). Publisher Copyright: {\textcopyright} 2016 The Author(s)",

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Alishekevitz, D, Gingis-Velitski, S, Kaidar-Person, O, Gutter-Kapon, L, Scherer, SD, Raviv, Z, Merquiol, E, Ben-Nun, Y, Miller, V, Rachman-Tzemah, C, Timaner, M, Mumblat, Y, Ilan, N, Loven, D, Hershkovitz, D, Satchi-Fainaro, R, Blum, G, P. Sleeman, J, Vlodavsky, I & Shaked, Y 2016, 'Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3', Cell Reports, vol. 17, no. 5, pp. 1344-1356. https://doi.org/10.1016/j.celrep.2016.09.083

TY - JOUR

T1 - Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3

AU - Alishekevitz, Dror

AU - Gingis-Velitski, Svetlana

AU - Kaidar-Person, Orit

AU - Gutter-Kapon, Lilach

AU - Scherer, Sandra D.

AU - Raviv, Ziv

AU - Merquiol, Emmanuelle

AU - Ben-Nun, Yael

AU - Miller, Valeria

AU - Rachman-Tzemah, Chen

AU - Timaner, Michael

AU - Mumblat, Yelena

AU - Ilan, Neta

AU - Loven, David

AU - Hershkovitz, Dov

AU - Satchi-Fainaro, Ronit

AU - Blum, Galia

AU - P. Sleeman, Jonathan

AU - Vlodavsky, Israel

AU - Shaked, Yuval

N1 - Funding Information: This study was supported by research grants from the European Research Council (under the FP-7 program, 260633 ), the Israel Science Foundation ( 490/12 ), and Israel Cancer Research Funds ( 708/12 ) (Y.S.). This study was also supported by research grants from the German Israel Foundation ( 1204-253.13/2012 ) (Y.S. and J.P.S.) and the Israeli Society for Clinical Oncology and Radiation Therapy (O.K.-P. and Y.S.). Publisher Copyright: © 2016 The Author(s)

PY - 2016/10/25

Y1 - 2016/10/25

N2 - 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.

AB - 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.

KW - VEGF-C

KW - chemotherapy

KW - host response

KW - lymphangiogenesis

KW - macrophages

KW - metastatis

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DO - 10.1016/j.celrep.2016.09.083

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AN - SCOPUS:84994759902

SN - 2211-1247

VL - 17

SP - 1344

EP - 1356

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

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

Abstract

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Keywords

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