Paclitaxel induces lymphatic endothelial cells autophagy to promote metastasis
Identifieur interne : 000077 ( Pmc/Curation ); précédent : 000076; suivant : 000078Paclitaxel induces lymphatic endothelial cells autophagy to promote metastasis
Auteurs : Audrey Zamora [France] ; Melinda Alves [France] ; Charlotte Chollet [France] ; Nicole Therville [France] ; Tiffany Fougeray [France] ; Florence Tatin [France] ; Camille Franchet [France] ; Anne Gomez-Brouchet [France] ; Charlotte Vaysse [France] ; Laurent O. Martinez [France] ; Souad Najib [France] ; Julie Guillermet-Guibert [France] ; Eric Lacazette [France] ; Anne-Catherine Prats [France] ; Barbara Garmy-Susini [France]Source :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Cytotoxic therapy for breast cancer inhibits the growth of primary tumors, but promotes metastasis to the sentinel lymph nodes through the lymphatic system. However, the effect of first-line chemotherapy on the lymphatic endothelium has been poorly investigated. In this study, we determined that paclitaxel, the anti-cancer drug approved for the treatment of metastatic or locally advanced breast cancer, induces lymphatic endothelial cell (LEC) autophagy to increase metastases. While paclitaxel treatment was largely efficacious in inhibiting LEC adhesion, it had no effect on cell survival. Paclitaxel inhibited LEC migration and branch point formation by inducing an autophagy mechanism independent of Akt phosphorylation. In vivo, paclitaxel mediated a higher permeability of lymphatic endothelium to tumor cells and this effect was reversed by chloroquine, an autophagy-lysosome inhibitor. Despite a strong effect on reducing tumor size, paclitaxel significantly increased metastasis to the sentinel lymph nodes. This effect was restricted to a lymphatic dissemination, as chemotherapy did not affect the blood endothelium. Taken together, our findings suggest that the lymphatic system resists to chemotherapy through an autophagy mechanism to promote malignant progression and metastatic lesions. This study paves the way for new combinative therapies aimed at reducing the number of metastases.
Url:
DOI: 10.1038/s41419-019-2181-1
PubMed: 31863036
PubMed Central: 6925245
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<author><name sortKey="Guillermet Guibert, Julie" sort="Guillermet Guibert, Julie" uniqKey="Guillermet Guibert J" first="Julie" last="Guillermet-Guibert">Julie Guillermet-Guibert</name>
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<author><name sortKey="Prats, Anne Catherine" sort="Prats, Anne Catherine" uniqKey="Prats A" first="Anne-Catherine" last="Prats">Anne-Catherine Prats</name>
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<series><title level="j">Cell Death & Disease</title>
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<front><div type="abstract" xml:lang="en"><p id="Par1">Cytotoxic therapy for breast cancer inhibits the growth of primary tumors, but promotes metastasis to the sentinel lymph nodes through the lymphatic system. However, the effect of first-line chemotherapy on the lymphatic endothelium has been poorly investigated. In this study, we determined that paclitaxel, the anti-cancer drug approved for the treatment of metastatic or locally advanced breast cancer, induces lymphatic endothelial cell (LEC) autophagy to increase metastases. While paclitaxel treatment was largely efficacious in inhibiting LEC adhesion, it had no effect on cell survival. Paclitaxel inhibited LEC migration and branch point formation by inducing an autophagy mechanism independent of Akt phosphorylation. In vivo, paclitaxel mediated a higher permeability of lymphatic endothelium to tumor cells and this effect was reversed by chloroquine, an autophagy-lysosome inhibitor. Despite a strong effect on reducing tumor size, paclitaxel significantly increased metastasis to the sentinel lymph nodes. This effect was restricted to a lymphatic dissemination, as chemotherapy did not affect the blood endothelium. Taken together, our findings suggest that the lymphatic system resists to chemotherapy through an autophagy mechanism to promote malignant progression and metastatic lesions. This study paves the way for new combinative therapies aimed at reducing the number of metastases.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id>
<journal-title-group><journal-title>Cell Death & Disease</journal-title>
</journal-title-group>
<issn pub-type="epub">2041-4889</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31863036</article-id>
<article-id pub-id-type="pmc">6925245</article-id>
<article-id pub-id-type="publisher-id">2181</article-id>
<article-id pub-id-type="doi">10.1038/s41419-019-2181-1</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Paclitaxel induces lymphatic endothelial cells autophagy to promote metastasis</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Zamora</surname>
<given-names>Audrey</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alves</surname>
<given-names>Melinda</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chollet</surname>
<given-names>Charlotte</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Therville</surname>
<given-names>Nicole</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fougeray</surname>
<given-names>Tiffany</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tatin</surname>
<given-names>Florence</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Franchet</surname>
<given-names>Camille</given-names>
</name>
<xref ref-type="aff" rid="Aff5">5</xref>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gomez-Brouchet</surname>
<given-names>Anne</given-names>
</name>
<xref ref-type="aff" rid="Aff5">5</xref>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vaysse</surname>
<given-names>Charlotte</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martinez</surname>
<given-names>Laurent O.</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Najib</surname>
<given-names>Souad</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-3173-4907</contrib-id>
<name><surname>Guillermet-Guibert</surname>
<given-names>Julie</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lacazette</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-5282-3776</contrib-id>
<name><surname>Prats</surname>
<given-names>Anne-Catherine</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Garmy-Susini</surname>
<given-names>Barbara</given-names>
</name>
<address><email>barbara.garmy-susini@inserm.fr</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
UMR1048-I2MC, Université de Toulouse, Inserm, UT3, Toulouse, France</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 1457 2980</institution-id>
<institution-id institution-id-type="GRID">grid.411175.7</institution-id>
<institution>Department of Gynecology Surgery,</institution>
<institution>University Hospital Centre—Toulouse, IUCT-Oncopole,</institution>
</institution-wrap>
Toulouse, France</aff>
<aff id="Aff3"><label>3</label>
UMR 1037-CRCT, Inserm, Université de Toulouse, UT3, Toulouse, France</aff>
<aff id="Aff4"><label>4</label>
INRA Toxalim, UT3, Toulouse, France</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 035X</institution-id>
<institution-id institution-id-type="GRID">grid.15781.3a</institution-id>
<institution>UMR 5089-IPBS, CNRS, UPS,</institution>
</institution-wrap>
Toulouse, France</aff>
<aff id="Aff6"><label>6</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.488470.7</institution-id>
<institution>Department of Pathology,</institution>
<institution>IUCT-Oncopole,</institution>
</institution-wrap>
Toulouse, France</aff>
</contrib-group>
<pub-date pub-type="epub"><day>20</day>
<month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>20</day>
<month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>12</month>
<year>2019</year>
</pub-date>
<volume>10</volume>
<issue>12</issue>
<elocation-id>956</elocation-id>
<history><date date-type="received"><day>10</day>
<month>5</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>1</day>
<month>10</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>25</day>
<month>10</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p id="Par1">Cytotoxic therapy for breast cancer inhibits the growth of primary tumors, but promotes metastasis to the sentinel lymph nodes through the lymphatic system. However, the effect of first-line chemotherapy on the lymphatic endothelium has been poorly investigated. In this study, we determined that paclitaxel, the anti-cancer drug approved for the treatment of metastatic or locally advanced breast cancer, induces lymphatic endothelial cell (LEC) autophagy to increase metastases. While paclitaxel treatment was largely efficacious in inhibiting LEC adhesion, it had no effect on cell survival. Paclitaxel inhibited LEC migration and branch point formation by inducing an autophagy mechanism independent of Akt phosphorylation. In vivo, paclitaxel mediated a higher permeability of lymphatic endothelium to tumor cells and this effect was reversed by chloroquine, an autophagy-lysosome inhibitor. Despite a strong effect on reducing tumor size, paclitaxel significantly increased metastasis to the sentinel lymph nodes. This effect was restricted to a lymphatic dissemination, as chemotherapy did not affect the blood endothelium. Taken together, our findings suggest that the lymphatic system resists to chemotherapy through an autophagy mechanism to promote malignant progression and metastatic lesions. This study paves the way for new combinative therapies aimed at reducing the number of metastases.</p>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>Breast cancer</kwd>
<kwd>Autophagy</kwd>
<kwd>Cancer</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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