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

被引：113

作者：

Alishekevitz, Dror ^{[1
]}

Gingis-Velitski, Svetlana ^{[1
]}

Kaidar-Person, Orit ^{[2
]}

Gutter-Kapon, Lilach ^{[1
]}

Scherer, Sandra D. ^{[3
,4
]}

Raviv, Ziv ^{[1
]}

Merquiol, Emmanuelle ^{[5
]}

Ben-Nun, Yael ^{[5
]}

Miller, Valeria ^{[1
]}

Rachman-Tzemah, Chen ^{[1
]}

Timaner, Michael ^{[1
]}

Mumblat, Yelena ^{[1
]}

Ilan, Neta ^{[1
]}

Loven, David ^{[6
]}

Hershkovitz, Dov ^{[7
]}

Satchi-Fainaro, Ronit ^{[8
]}

Blum, Galia ^{[5
]}

Sleeman, Jonathan P. ^{[3
,4
]}

Vlodavsky, Israel ^{[1
]}

Shaked, Yuval ^{[1
]}

机构：

[1] Technion Israel Inst Technol, Rappaport Fac Med, Dept Cell Biol & Canc Sci, IL-3109601 Haifa, Israel

[2] Rambam Hlth Care Campus, Div Oncol, IL-3109601 Haifa, Israel

[3] Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76344 Eggenstein Leopoldshafen, Germany

[4] Heidelberg Univ, Med Fac Mannheim, Ctr Biomed & Med Technol Mannheim CBTM, D-68167 Mannheim, Germany

[5] Hebrew Univ Jerusalem, Sch Pharm, Fac Med, IL-9112001 Jerusalem, Israel

[6] HaEmek Med Ctr, Dept Oncol, IL-1834111 Afula, Israel

[7] Rambam Hlth Care Campus, Dept Pathol, IL-3109601 Haifa, Israel

[8] Tel Aviv Univ, Dept Pharmacol, Fac Med, IL-6997801 Tel Aviv, Israel

来源：

CELL REPORTS | 2016年 / 17卷 / 05期

基金：

欧洲研究理事会; 以色列科学基金会;

关键词：

GROWTH-FACTOR RECEPTOR-3; BREAST-CANCER; TUMOR LYMPHANGIOGENESIS; MICE; ANGIOGENESIS; HEPARANASE; CELLS; ACTIVATION; INHIBITION; EXPRESSION;

D O I：

10.1016/j.celrep.2016.09.083

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：1344 / 1356

页数：13

共 44 条

[1]

Differential Therapeutic Effects of Anti-VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing [J].

Alishekevitz, Dror ;

Bril, Rotem ;

Loven, David ;

Miller, Valeria ;

Voloshin, Tali ;

Gingis-Velistki, Svetlana ;

Fremder, Ella ;

Scherer, Stefan J. ;

Shaked, Yuval .

MOLECULAR CANCER THERAPEUTICS, 2014, 13 (01) :202-213

[2]

Interaction of tumor cells and lymphatic vessels in cancer progression [J].

Alitalo, A. ;

Detmar, M. .

ONCOGENE, 2012, 31 (42) :4499-4508

[3]

Molecular mechanisms of lymphangiogenesis in health and disease [J].

Alitalo, K ;

Carmeliet, P .

CANCER CELL, 2002, 1 (03) :219-227

[4]

The heparanase system and tumor metastasis: is heparanase the seed and soil? [J].

Arvatz, Gil ;

Shafat, Itay ;

Levy-Adam, Flonia ;

Ilan, Neta ;

Vlodavsky, Israel .

CANCER AND METASTASIS REVIEWS, 2011, 30 (02) :253-268

[5]

SEQUENTIAL DEGRADATION OF HEPARAN-SULFATE IN THE SUBENDOTHELIAL EXTRACELLULAR-MATRIX BY HIGHLY METASTATIC LYMPHOMA-CELLS [J].

BARNER, M ;

KRAMER, MD ;

SCHIRRMACHER, V ;

ISHAIMICHAELI, R ;

FUKS, Z ;

VLODAVSKY, I .

INTERNATIONAL JOURNAL OF CANCER, 1985, 35 (04) :483-491

[6]

Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands [J].

Chung, Eui-Sang ;

Chauhan, Sunil Kumar ;

Jin, Yiping ;

Nakao, Shintaro ;

Hafezi-Moghadam, Ali ;

van Rooijen, Nico ;

Zhang, Qiang ;

Chen, Lu ;

Dana, Reza .

AMERICAN JOURNAL OF PATHOLOGY, 2009, 175 (05) :1984-1992

[7]

Heparanase induces VEGF C and facilitates tumor lymphangiogenesis [J].

Cohen-Kaplan, Victoria ;

Naroditsky, Inna ;

Zetser, Anna ;

Illan, Neta ;

Vlodavsky, Israel ;

Doweck, Ilana .

INTERNATIONAL JOURNAL OF CANCER, 2008, 123 (11) :2566-2573

[8]

Macrophage Regulation of Tumor Responses to Anticancer Therapies [J].

De Palma, Michele ;

Lewis, Claire E. .

CANCER CELL, 2013, 23 (03) :277-286

[9]

FISHER ER, 1983, CANCER-AM CANCER SOC, V51, P181, DOI 10.1002/1097-0142(19830115)51:2<181::AID-CNCR2820510202>3.0.CO

[10]

2-A

← 1 2 3 4 5 →