Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3
Identifieur interne : 000E31 ( Main/Exploration ); précédent : 000E30; suivant : 000E32Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3
Auteurs : Dror Alishekevitz [Israël] ; Svetlana Gingis-Velitski [Israël] ; Orit Kaidar-Person [Israël] ; Lilach Gutter-Kapon [Israël] ; Sandra D. Scherer [Allemagne] ; Ziv Raviv [Israël] ; Emmanuelle Merquiol [Israël] ; Yael Ben-Nun [Israël] ; Valeria Miller [Israël] ; Chen Rachman-Tzemah [Israël] ; Michael Timaner [Israël] ; Yelena Mumblat [Israël] ; Neta Ilan [Israël] ; David Loven [Israël] ; Dov Hershkovitz [Israël] ; Ronit Satchi-Fainaro [Israël] ; Galia Blum [Israël] ; Jonathan P. Sleeman [Allemagne] ; Israel Vlodavsky [Israël] ; Yuval Shaked [Israël]Source :
- Cell Reports [ 2211-1247 ] ; 2016.
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.
Url:
DOI: 10.1016/j.celrep.2016.09.083
PubMed: 27783948
PubMed Central: 5098117
Affiliations:
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uniqKey="Miller V" first="Valeria" last="Miller">Valeria Miller</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Rachman Tzemah, Chen" sort="Rachman Tzemah, Chen" uniqKey="Rachman Tzemah C" first="Chen" last="Rachman-Tzemah">Chen Rachman-Tzemah</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Timaner, Michael" sort="Timaner, Michael" uniqKey="Timaner M" first="Michael" last="Timaner">Michael Timaner</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Mumblat, Yelena" sort="Mumblat, Yelena" uniqKey="Mumblat Y" first="Yelena" last="Mumblat">Yelena Mumblat</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Ilan, Neta" sort="Ilan, Neta" uniqKey="Ilan N" first="Neta" last="Ilan">Neta Ilan</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Loven, David" sort="Loven, David" uniqKey="Loven D" first="David" last="Loven">David Loven</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Oncology, Ha’Emek Medical Center, 1834111 Afula, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Oncology, Ha’Emek Medical Center, 1834111 Afula</wicri:regionArea><wicri:noRegion>1834111 Afula</wicri:noRegion></affiliation></author><author><name sortKey="Hershkovitz, Dov" sort="Hershkovitz, Dov" uniqKey="Hershkovitz D" first="Dov" last="Hershkovitz">Dov Hershkovitz</name><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Pathology, Rambam Health Care Campus, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Pathology, Rambam Health Care Campus, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Satchi Fainaro, Ronit" sort="Satchi Fainaro, Ronit" uniqKey="Satchi Fainaro R" first="Ronit" last="Satchi-Fainaro">Ronit Satchi-Fainaro</name><affiliation wicri:level="1"><nlm:aff id="aff8">Department of Pharmacology, Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Pharmacology, Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv</wicri:regionArea><wicri:noRegion>6997801 Tel Aviv</wicri:noRegion></affiliation></author><author><name sortKey="Blum, Galia" sort="Blum, Galia" uniqKey="Blum G" first="Galia" last="Blum">Galia Blum</name><affiliation wicri:level="1"><nlm:aff id="aff5">The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 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Sleeman</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen</wicri:regionArea><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff4">Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 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Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Gingis Velitski, Svetlana" sort="Gingis Velitski, Svetlana" uniqKey="Gingis Velitski S" first="Svetlana" last="Gingis-Velitski">Svetlana Gingis-Velitski</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Kaidar Person, Orit" sort="Kaidar Person, Orit" uniqKey="Kaidar Person O" first="Orit" last="Kaidar-Person">Orit Kaidar-Person</name><affiliation wicri:level="1"><nlm:aff id="aff2">Division of Oncology, Rambam Health Care Campus, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Division of Oncology, Rambam Health Care Campus, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Gutter Kapon, Lilach" sort="Gutter Kapon, Lilach" uniqKey="Gutter Kapon L" first="Lilach" last="Gutter-Kapon">Lilach Gutter-Kapon</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Scherer, Sandra D" sort="Scherer, Sandra D" uniqKey="Scherer S" first="Sandra D." last="Scherer">Sandra D. Scherer</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen</wicri:regionArea><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff4">Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author><author><name sortKey="Raviv, Ziv" sort="Raviv, Ziv" uniqKey="Raviv Z" first="Ziv" last="Raviv">Ziv Raviv</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Merquiol, Emmanuelle" sort="Merquiol, Emmanuelle" uniqKey="Merquiol E" first="Emmanuelle" last="Merquiol">Emmanuelle Merquiol</name><affiliation wicri:level="1"><nlm:aff id="aff5">The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem</wicri:regionArea><wicri:noRegion>9112001 Jerusalem</wicri:noRegion></affiliation></author><author><name sortKey="Ben Nun, Yael" sort="Ben Nun, Yael" uniqKey="Ben Nun Y" first="Yael" last="Ben-Nun">Yael Ben-Nun</name><affiliation wicri:level="1"><nlm:aff id="aff5">The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem</wicri:regionArea><wicri:noRegion>9112001 Jerusalem</wicri:noRegion></affiliation></author><author><name sortKey="Miller, Valeria" sort="Miller, Valeria" uniqKey="Miller V" first="Valeria" last="Miller">Valeria Miller</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Rachman Tzemah, Chen" sort="Rachman Tzemah, Chen" uniqKey="Rachman Tzemah C" first="Chen" last="Rachman-Tzemah">Chen Rachman-Tzemah</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Timaner, Michael" sort="Timaner, Michael" uniqKey="Timaner M" first="Michael" last="Timaner">Michael Timaner</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Mumblat, Yelena" sort="Mumblat, Yelena" uniqKey="Mumblat Y" first="Yelena" last="Mumblat">Yelena Mumblat</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Ilan, Neta" sort="Ilan, Neta" uniqKey="Ilan N" first="Neta" last="Ilan">Neta Ilan</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Loven, David" sort="Loven, David" uniqKey="Loven D" first="David" last="Loven">David Loven</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Oncology, Ha’Emek Medical Center, 1834111 Afula, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Oncology, Ha’Emek Medical Center, 1834111 Afula</wicri:regionArea><wicri:noRegion>1834111 Afula</wicri:noRegion></affiliation></author><author><name sortKey="Hershkovitz, Dov" sort="Hershkovitz, Dov" uniqKey="Hershkovitz D" first="Dov" last="Hershkovitz">Dov Hershkovitz</name><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Pathology, Rambam Health Care Campus, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Pathology, Rambam Health Care Campus, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Satchi Fainaro, Ronit" sort="Satchi Fainaro, Ronit" uniqKey="Satchi Fainaro R" first="Ronit" last="Satchi-Fainaro">Ronit Satchi-Fainaro</name><affiliation wicri:level="1"><nlm:aff id="aff8">Department of Pharmacology, Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Pharmacology, Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv</wicri:regionArea><wicri:noRegion>6997801 Tel Aviv</wicri:noRegion></affiliation></author><author><name sortKey="Blum, Galia" sort="Blum, Galia" uniqKey="Blum G" first="Galia" last="Blum">Galia Blum</name><affiliation wicri:level="1"><nlm:aff id="aff5">The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem</wicri:regionArea><wicri:noRegion>9112001 Jerusalem</wicri:noRegion></affiliation></author><author><name sortKey="P Sleeman, Jonathan" sort="P Sleeman, Jonathan" uniqKey="P Sleeman J" first="Jonathan" last="P. Sleeman">Jonathan P. Sleeman</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen</wicri:regionArea><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion><wicri:noRegion>76344 Eggenstein-Leopoldshafen</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff4">Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author><author><name sortKey="Vlodavsky, Israel" sort="Vlodavsky, Israel" uniqKey="Vlodavsky I" first="Israel" last="Vlodavsky">Israel Vlodavsky</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author><author><name sortKey="Shaked, Yuval" sort="Shaked, Yuval" uniqKey="Shaked Y" first="Yuval" last="Shaked">Yuval Shaked</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa, Israel</nlm:aff><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 3109601 Haifa</wicri:regionArea><wicri:noRegion>3109601 Haifa</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cell Reports</title><idno type="eISSN">2211-1247</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Alishekevitz, D" uniqKey="Alishekevitz D">D. 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Duan</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li><li>Israël</li></country><region><li>Bade-Wurtemberg</li><li>District de Karlsruhe</li></region><settlement><li>Mannheim</li></settlement></list><tree><country name="Israël"><noRegion><name sortKey="Alishekevitz, Dror" sort="Alishekevitz, Dror" uniqKey="Alishekevitz D" first="Dror" last="Alishekevitz">Dror Alishekevitz</name></noRegion><name sortKey="Ben Nun, Yael" sort="Ben Nun, Yael" uniqKey="Ben Nun Y" first="Yael" last="Ben-Nun">Yael Ben-Nun</name><name sortKey="Blum, Galia" sort="Blum, Galia" uniqKey="Blum G" first="Galia" last="Blum">Galia Blum</name><name sortKey="Gingis Velitski, Svetlana" sort="Gingis Velitski, Svetlana" uniqKey="Gingis Velitski S" first="Svetlana" last="Gingis-Velitski">Svetlana Gingis-Velitski</name><name sortKey="Gutter Kapon, Lilach" sort="Gutter Kapon, Lilach" uniqKey="Gutter Kapon L" first="Lilach" last="Gutter-Kapon">Lilach Gutter-Kapon</name><name sortKey="Hershkovitz, Dov" sort="Hershkovitz, Dov" uniqKey="Hershkovitz D" first="Dov" last="Hershkovitz">Dov Hershkovitz</name><name sortKey="Ilan, Neta" sort="Ilan, Neta" uniqKey="Ilan N" first="Neta" last="Ilan">Neta Ilan</name><name sortKey="Kaidar Person, Orit" sort="Kaidar Person, Orit" uniqKey="Kaidar Person O" first="Orit" last="Kaidar-Person">Orit Kaidar-Person</name><name sortKey="Loven, David" sort="Loven, David" uniqKey="Loven D" first="David" last="Loven">David Loven</name><name sortKey="Merquiol, Emmanuelle" sort="Merquiol, Emmanuelle" uniqKey="Merquiol E" first="Emmanuelle" last="Merquiol">Emmanuelle Merquiol</name><name sortKey="Miller, Valeria" sort="Miller, Valeria" uniqKey="Miller V" first="Valeria" last="Miller">Valeria Miller</name><name sortKey="Mumblat, Yelena" sort="Mumblat, Yelena" uniqKey="Mumblat Y" first="Yelena" last="Mumblat">Yelena Mumblat</name><name sortKey="Rachman Tzemah, Chen" sort="Rachman Tzemah, Chen" uniqKey="Rachman Tzemah C" first="Chen" last="Rachman-Tzemah">Chen Rachman-Tzemah</name><name sortKey="Raviv, Ziv" sort="Raviv, Ziv" uniqKey="Raviv Z" first="Ziv" last="Raviv">Ziv Raviv</name><name sortKey="Satchi Fainaro, Ronit" sort="Satchi Fainaro, Ronit" uniqKey="Satchi Fainaro R" first="Ronit" last="Satchi-Fainaro">Ronit Satchi-Fainaro</name><name sortKey="Shaked, Yuval" sort="Shaked, Yuval" uniqKey="Shaked Y" first="Yuval" last="Shaked">Yuval Shaked</name><name sortKey="Timaner, Michael" sort="Timaner, Michael" uniqKey="Timaner M" first="Michael" last="Timaner">Michael Timaner</name><name sortKey="Vlodavsky, Israel" sort="Vlodavsky, Israel" uniqKey="Vlodavsky I" first="Israel" last="Vlodavsky">Israel Vlodavsky</name></country><country name="Allemagne"><noRegion><name sortKey="Scherer, Sandra D" sort="Scherer, Sandra D" uniqKey="Scherer S" first="Sandra D." last="Scherer">Sandra D. Scherer</name></noRegion><name sortKey="P Sleeman, Jonathan" sort="P Sleeman, Jonathan" uniqKey="P Sleeman J" first="Jonathan" last="P. Sleeman">Jonathan P. Sleeman</name><name sortKey="P Sleeman, Jonathan" sort="P Sleeman, Jonathan" uniqKey="P Sleeman J" first="Jonathan" last="P. Sleeman">Jonathan P. Sleeman</name><name sortKey="Scherer, Sandra D" sort="Scherer, Sandra D" uniqKey="Scherer S" first="Sandra D." last="Scherer">Sandra D. Scherer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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