Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
Identifieur interne : 000760 ( Ncbi/Merge ); précédent : 000759; suivant : 000761Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
Auteurs : Iris Uribesalgo ; David Hoffmann ; Yin Zhang ; Anoop Kavirayani ; Jelena Lazovic ; Judit Berta ; Maria Novatchkova ; Tsung-Pin Pai ; Reiner A. Wimmer ; Vikt Ria Lászl ; Daniel Schramek ; Rezaul Karim ; Luigi Tortola ; Sumit Deswal ; Lisa Haas ; Johannes Zuber ; Mikl S Sz Cs ; Keiji Kuba ; Balazs Dome ; Yihai Cao ; Bernhard J. Haubner ; Josef M. PenningerSource :
- EMBO Molecular Medicine [ 1757-4676 ] ; 2019.
Abstract
Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti‐angiogenic treatment has limited efficacy due to therapy‐induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy‐induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid‐derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti‐angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor‐induced metastases, and high Apelin levels correlate with poor prognosis of anti‐angiogenic therapy patients. These data identify a druggable anti‐angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.
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DOI: 10.15252/emmm.201809266
PubMed: 31267692
PubMed Central: 6685079
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Wimmer</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Laszl, Vikt Ria" sort="Laszl, Vikt Ria" uniqKey="Laszl V" first="Vikt Ria" last="Lászl">Vikt Ria Lászl</name><affiliation><nlm:aff id="emmm201809266-aff-0007"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0008"></nlm:aff></affiliation></author><author><name sortKey="Schramek, Daniel" sort="Schramek, Daniel" uniqKey="Schramek D" first="Daniel" last="Schramek">Daniel Schramek</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0009"></nlm:aff></affiliation></author><author><name sortKey="Karim, Rezaul" sort="Karim, Rezaul" uniqKey="Karim R" first="Rezaul" last="Karim">Rezaul Karim</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Tortola, Luigi" sort="Tortola, Luigi" uniqKey="Tortola L" first="Luigi" last="Tortola">Luigi Tortola</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Deswal, Sumit" sort="Deswal, Sumit" uniqKey="Deswal S" first="Sumit" last="Deswal">Sumit Deswal</name><affiliation><nlm:aff id="emmm201809266-aff-0010"></nlm:aff></affiliation></author><author><name sortKey="Haas, Lisa" sort="Haas, Lisa" uniqKey="Haas L" first="Lisa" last="Haas">Lisa Haas</name><affiliation><nlm:aff id="emmm201809266-aff-0010"></nlm:aff></affiliation></author><author><name sortKey="Zuber, Johannes" sort="Zuber, Johannes" uniqKey="Zuber J" first="Johannes" last="Zuber">Johannes Zuber</name><affiliation><nlm:aff id="emmm201809266-aff-0010"></nlm:aff></affiliation></author><author><name sortKey="Sz Cs, Mikl S" sort="Sz Cs, Mikl S" uniqKey="Sz Cs M" first="Mikl S" last="Sz Cs">Mikl S Sz Cs</name><affiliation><nlm:aff id="emmm201809266-aff-0011"></nlm:aff></affiliation></author><author><name sortKey="Kuba, Keiji" sort="Kuba, Keiji" uniqKey="Kuba K" first="Keiji" last="Kuba">Keiji Kuba</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0012"></nlm:aff></affiliation></author><author><name sortKey="Dome, Balazs" sort="Dome, Balazs" uniqKey="Dome B" first="Balazs" last="Dome">Balazs Dome</name><affiliation><nlm:aff id="emmm201809266-aff-0006"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0007"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0013"></nlm:aff></affiliation></author><author><name sortKey="Cao, Yihai" sort="Cao, Yihai" uniqKey="Cao Y" first="Yihai" last="Cao">Yihai Cao</name><affiliation><nlm:aff id="emmm201809266-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Haubner, Bernhard J" sort="Haubner, Bernhard J" uniqKey="Haubner B" first="Bernhard J" last="Haubner">Bernhard J. Haubner</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0014"></nlm:aff></affiliation></author><author><name sortKey="Penninger, Josef M" sort="Penninger, Josef M" uniqKey="Penninger J" first="Josef M" last="Penninger">Josef M. Penninger</name><affiliation><nlm:aff id="emmm201809266-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="emmm201809266-aff-0015"></nlm:aff></affiliation></author></analytic><series><title level="j">EMBO Molecular Medicine</title><idno type="ISSN">1757-4676</idno><idno type="eISSN">1757-4684</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti‐angiogenic treatment has limited efficacy due to therapy‐induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy‐induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid‐derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti‐angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor‐induced metastases, and high Apelin levels correlate with poor prognosis of anti‐angiogenic therapy patients. These data identify a druggable anti‐angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">EMBO Mol Med</journal-id><journal-id journal-id-type="iso-abbrev">EMBO Mol Med</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)1757-4684</journal-id><journal-id journal-id-type="publisher-id">EMMM</journal-id><journal-id journal-id-type="hwp">embomm</journal-id><journal-title-group><journal-title>EMBO Molecular Medicine</journal-title></journal-title-group><issn pub-type="ppub">1757-4676</issn><issn pub-type="epub">1757-4684</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31267692</article-id><article-id pub-id-type="pmc">6685079</article-id><article-id pub-id-type="doi">10.15252/emmm.201809266</article-id><article-id pub-id-type="publisher-id">EMMM201809266</article-id><article-categories><subj-group subj-group-type="overline"><subject>Article</subject></subj-group><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy</article-title><alt-title alt-title-type="left-running-head">Iris Uribesalgo <italic>et al</italic></alt-title></title-group><contrib-group><contrib id="emmm201809266-cr-0001" contrib-type="author" corresp="yes"><name><surname>Uribesalgo</surname><given-names>Iris</given-names></name><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-9492-1000</contrib-id><address><email>iris.uribesalgo@imba.oeaw.ac.at</email></address><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref><xref ref-type="author-notes" rid="emmm201809266-note-1001"><sup>†</sup></xref></contrib><contrib id="emmm201809266-cr-0002" contrib-type="author"><name><surname>Hoffmann</surname><given-names>David</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref><xref ref-type="author-notes" rid="emmm201809266-note-1001"><sup>†</sup></xref></contrib><contrib id="emmm201809266-cr-0003" contrib-type="author"><name><surname>Zhang</surname><given-names>Yin</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0002"><sup>2</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0003"><sup>3</sup></xref></contrib><contrib id="emmm201809266-cr-0004" contrib-type="author"><name><surname>Kavirayani</surname><given-names>Anoop</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0004"><sup>4</sup></xref></contrib><contrib id="emmm201809266-cr-0005" contrib-type="author"><name><surname>Lazovic</surname><given-names>Jelena</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0005"><sup>5</sup></xref></contrib><contrib id="emmm201809266-cr-0006" contrib-type="author"><name><surname>Berta</surname><given-names>Judit</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0006"><sup>6</sup></xref></contrib><contrib id="emmm201809266-cr-0007" contrib-type="author"><name><surname>Novatchkova</surname><given-names>Maria</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref></contrib><contrib id="emmm201809266-cr-0008" contrib-type="author"><name><surname>Pai</surname><given-names>Tsung‐Pin</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref></contrib><contrib id="emmm201809266-cr-0009" contrib-type="author"><name><surname>Wimmer</surname><given-names>Reiner A</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref></contrib><contrib id="emmm201809266-cr-0010" contrib-type="author"><name><surname>László</surname><given-names>Viktória</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0007"><sup>7</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0008"><sup>8</sup></xref></contrib><contrib id="emmm201809266-cr-0011" contrib-type="author"><name><surname>Schramek</surname><given-names>Daniel</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0009"><sup>9</sup></xref></contrib><contrib id="emmm201809266-cr-0012" contrib-type="author"><name><surname>Karim</surname><given-names>Rezaul</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref></contrib><contrib id="emmm201809266-cr-0013" contrib-type="author"><name><surname>Tortola</surname><given-names>Luigi</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref></contrib><contrib id="emmm201809266-cr-0014" contrib-type="author"><name><surname>Deswal</surname><given-names>Sumit</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0010"><sup>10</sup></xref></contrib><contrib id="emmm201809266-cr-0015" contrib-type="author"><name><surname>Haas</surname><given-names>Lisa</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0010"><sup>10</sup></xref></contrib><contrib id="emmm201809266-cr-0016" contrib-type="author"><name><surname>Zuber</surname><given-names>Johannes</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0010"><sup>10</sup></xref></contrib><contrib id="emmm201809266-cr-0017" contrib-type="author"><name><surname>Szűcs</surname><given-names>Miklós</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0011"><sup>11</sup></xref></contrib><contrib id="emmm201809266-cr-0018" contrib-type="author"><name><surname>Kuba</surname><given-names>Keiji</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0012"><sup>12</sup></xref></contrib><contrib id="emmm201809266-cr-0019" contrib-type="author"><name><surname>Dome</surname><given-names>Balazs</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0006"><sup>6</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0007"><sup>7</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0013"><sup>13</sup></xref></contrib><contrib id="emmm201809266-cr-0020" contrib-type="author"><name><surname>Cao</surname><given-names>Yihai</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0002"><sup>2</sup></xref></contrib><contrib id="emmm201809266-cr-0021" contrib-type="author"><name><surname>Haubner</surname><given-names>Bernhard J</given-names></name><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0014"><sup>14</sup></xref></contrib><contrib id="emmm201809266-cr-0022" contrib-type="author" corresp="yes"><name><surname>Penninger</surname><given-names>Josef M</given-names></name><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8194-3777</contrib-id><address><email>josef.penninger@imba.oeaw.ac.at</email></address><xref ref-type="aff" rid="emmm201809266-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="emmm201809266-aff-0015"><sup>15</sup></xref></contrib></contrib-group><aff id="emmm201809266-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)</named-content><institution>Vienna BioCenter</institution><named-content content-type="city">Vienna</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Department of Microbiology, Tumor and Cell Biology</named-content><named-content content-type="organisation-division">Biomedicum</named-content><institution>Karolinska Institutet</institution><named-content content-type="city">Stockholm</named-content><country country="SE">Sweden</country></aff><aff id="emmm201809266-aff-0003"><label><sup>3</sup></label><named-content content-type="organisation-division">Medicine and Pharmacy Research Center</named-content><institution>Binzhou Medical University</institution><named-content content-type="city">Yantai</named-content><named-content content-type="country-part">Shandong Province</named-content><country country="CN">China</country></aff><aff id="emmm201809266-aff-0004"><label><sup>4</sup></label><named-content content-type="organisation-division">VBCF Histopathology</named-content><institution>Vienna BioCenter</institution><named-content content-type="city">Vienna</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0005"><label><sup>5</sup></label><named-content content-type="organisation-division">VBCF Preclinical Imaging</named-content><institution>Vienna BioCenter</institution><named-content content-type="city">Vienna</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0006"><label><sup>6</sup></label><named-content content-type="organisation-division">Department of Tumor Biology</named-content><institution>National Koranyi Institute of Pulmonology</institution><named-content content-type="city">Budapest</named-content><country country="HU">Hungary</country></aff><aff id="emmm201809266-aff-0007"><label><sup>7</sup></label><named-content content-type="organisation-division">Division of Thoracic Surgery</named-content><named-content content-type="organisation-division">Department of Surgery</named-content><named-content content-type="organisation-division">Comprehensive Cancer Center</named-content><institution>Medical University of Vienna</institution><named-content content-type="city">Vienna</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0008"><label><sup>8</sup></label><named-content content-type="organisation-division">Division of Molecular and Gender Imaging</named-content><named-content content-type="organisation-division">Department of Biomedical Imaging and Image‐guided Therapy</named-content><institution>Medical University of Vienna</institution><named-content content-type="city">Vienna</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0009"><label><sup>9</sup></label><named-content content-type="organisation-division">Department of Molecular Genetics</named-content><named-content content-type="organisation-division">Lunenfeld‐Tanenbaum Research Institute</named-content><named-content content-type="organisation-division">Mount Sinai Hospital</named-content><institution>University of Toronto</institution><named-content content-type="city">Toronto</named-content><named-content content-type="country-part">ON</named-content><country country="CA">Canada</country></aff><aff id="emmm201809266-aff-0010"><label><sup>10</sup></label><named-content content-type="organisation-division">Institute of Molecular Pathology (IMP)</named-content><institution>Vienna BioCenter</institution><named-content content-type="city">Vienna</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0011"><label><sup>11</sup></label><named-content content-type="organisation-division">Department of Urology</named-content><institution>Semmelweis University</institution><named-content content-type="city">Budapest</named-content><country country="HU">Hungary</country></aff><aff id="emmm201809266-aff-0012"><label><sup>12</sup></label><named-content content-type="organisation-division">Department Biochemistry and Metabolic Science</named-content><institution>Akita University Graduate School of Medicine</institution><named-content content-type="city">Akita</named-content><country country="JP">Japan</country></aff><aff id="emmm201809266-aff-0013"><label><sup>13</sup></label><named-content content-type="organisation-division">Department of Thoracic Surgery</named-content><institution>National Institute of Oncology‐Semmelweis University</institution><named-content content-type="city">Budapest</named-content><country country="HU">Hungary</country></aff><aff id="emmm201809266-aff-0014"><label><sup>14</sup></label><named-content content-type="organisation-division">Department of Internal Medicine III (Cardiology and Angiology)</named-content><institution>Medical University of Innsbruck</institution><named-content content-type="city">Innsbruck</named-content><country country="AT">Austria</country></aff><aff id="emmm201809266-aff-0015"><label><sup>15</sup></label><named-content content-type="organisation-division">Department of Medical Genetics</named-content><named-content content-type="organisation-division">Life Science Institute</named-content><institution>University of British Columbia</institution><named-content content-type="city">Vancouver</named-content><named-content content-type="country-part">BC</named-content><country country="CA">Canada</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label>Corresponding author. Tel: +43 (1)790 44; E‐mail: <email>iris.uribesalgo@imba.oeaw.ac.at</email><break></break>Corresponding author. Tel: +43 (1)790 44; E‐mail: <email>josef.penninger@imba.oeaw.ac.at</email><break></break></corresp><fn fn-type="equal" id="emmm201809266-note-1001"><label>†</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="epub"><day>24</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="ppub"><month>8</month><year>2019</year></pub-date><volume>11</volume><issue>8</issue><issue-id pub-id-type="doi">10.1002/emmm.v11.8</issue-id><elocation-id>e9266</elocation-id><history><date date-type="received"><day>25</day><month>4</month><year>2018</year></date><date date-type="rev-recd"><day>22</day><month>5</month><year>2019</year></date><date date-type="accepted"><day>28</day><month>5</month><year>2019</year></date></history><permissions><pmc-comment> © 2019 EMBO </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. Published under the terms of the CC BY 4.0 license</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <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, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="file:EMMM-11-e9266.pdf"></self-uri><abstract id="emmm201809266-abs-0001"><title>Abstract</title><p>Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti‐angiogenic treatment has limited efficacy due to therapy‐induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy‐induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid‐derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti‐angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor‐induced metastases, and high Apelin levels correlate with poor prognosis of anti‐angiogenic therapy patients. These data identify a druggable anti‐angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.</p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="emmm201809266-kwd-0001">anti‐angiogenic therapy</kwd><kwd id="emmm201809266-kwd-0002">Apelin–Apelin receptor</kwd><kwd id="emmm201809266-kwd-0003">therapy‐induced resistance</kwd><kwd id="emmm201809266-kwd-0004">tumor angiogenesis</kwd><kwd id="emmm201809266-kwd-0005">VEGF‐VEGFR</kwd></kwd-group><kwd-group kwd-group-type="subject-categories"><title>Subject Categories</title><kwd>Cancer</kwd><kwd>Vascular Biology & Angiogenesis</kwd></kwd-group><funding-group><award-group><funding-source>EMBO Long‐term Fellowship</funding-source></award-group><award-group><funding-source>Era of Hope Innovator award</funding-source></award-group><award-group><funding-source>Marie Curie Fellowship</funding-source></award-group><award-group><funding-source>Hungarian National Research, Development and Innovation Office</funding-source><award-id>PD111656</award-id><award-id>K109626</award-id><award-id>KNN121510</award-id></award-group><award-group><funding-source>Janos Bolyai Research Scholarship</funding-source></award-group><award-group><funding-source>IMBA</funding-source></award-group><award-group><funding-source>Austrian Ministry of Sciences</funding-source></award-group><award-group><funding-source>Austrian Academy of Sciences</funding-source></award-group><award-group><funding-source>ERC Advanced Grant</funding-source></award-group><award-group><funding-source>T. von Zastrow Foundation</funding-source></award-group></funding-group><counts><fig-count count="11"></fig-count><table-count count="0"></table-count><page-count count="19"></page-count><word-count count="15446"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>component-id</meta-name><meta-value>emmm201809266</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>August 2019</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:07.08.2019</meta-value></custom-meta></custom-meta-group></article-meta><notes><p content-type="self-citation"><mixed-citation publication-type="journal" id="emmm201809266-cit-1001"><source xml:lang="en">EMBO Mol Med</source> (<year>2019</year>) <volume>11</volume>: <elocation-id>e9266</elocation-id></mixed-citation></p><fn-group id="emmm201809266-ntgp-0001"><fn id="emmm201809266-note-1002"><p>See also: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.15252/emmm.201910892">L Claesson‐Welsh</ext-link> (August 2019)</p></fn></fn-group></notes></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Berta, Judit" sort="Berta, Judit" uniqKey="Berta J" first="Judit" last="Berta">Judit Berta</name><name sortKey="Cao, Yihai" sort="Cao, Yihai" uniqKey="Cao Y" first="Yihai" last="Cao">Yihai Cao</name><name sortKey="Deswal, Sumit" sort="Deswal, Sumit" uniqKey="Deswal S" first="Sumit" last="Deswal">Sumit Deswal</name><name sortKey="Dome, Balazs" sort="Dome, Balazs" uniqKey="Dome B" first="Balazs" last="Dome">Balazs Dome</name><name sortKey="Haas, Lisa" sort="Haas, Lisa" uniqKey="Haas L" first="Lisa" last="Haas">Lisa Haas</name><name sortKey="Haubner, Bernhard J" sort="Haubner, Bernhard J" uniqKey="Haubner B" first="Bernhard J" last="Haubner">Bernhard J. Haubner</name><name sortKey="Hoffmann, David" sort="Hoffmann, David" uniqKey="Hoffmann D" first="David" last="Hoffmann">David Hoffmann</name><name sortKey="Karim, Rezaul" sort="Karim, Rezaul" uniqKey="Karim R" first="Rezaul" last="Karim">Rezaul Karim</name><name sortKey="Kavirayani, Anoop" sort="Kavirayani, Anoop" uniqKey="Kavirayani A" first="Anoop" last="Kavirayani">Anoop Kavirayani</name><name sortKey="Kuba, Keiji" sort="Kuba, Keiji" uniqKey="Kuba K" first="Keiji" last="Kuba">Keiji Kuba</name><name sortKey="Laszl, Vikt Ria" sort="Laszl, Vikt Ria" uniqKey="Laszl V" first="Vikt Ria" last="Lászl">Vikt Ria Lászl</name><name sortKey="Lazovic, Jelena" sort="Lazovic, Jelena" uniqKey="Lazovic J" first="Jelena" last="Lazovic">Jelena Lazovic</name><name sortKey="Novatchkova, Maria" sort="Novatchkova, Maria" uniqKey="Novatchkova M" first="Maria" last="Novatchkova">Maria Novatchkova</name><name sortKey="Pai, Tsung In" sort="Pai, Tsung In" uniqKey="Pai T" first="Tsung-Pin" last="Pai">Tsung-Pin Pai</name><name sortKey="Penninger, Josef M" sort="Penninger, Josef M" uniqKey="Penninger J" first="Josef M" last="Penninger">Josef M. Penninger</name><name sortKey="Schramek, Daniel" sort="Schramek, Daniel" uniqKey="Schramek D" first="Daniel" last="Schramek">Daniel Schramek</name><name sortKey="Sz Cs, Mikl S" sort="Sz Cs, Mikl S" uniqKey="Sz Cs M" first="Mikl S" last="Sz Cs">Mikl S Sz Cs</name><name sortKey="Tortola, Luigi" sort="Tortola, Luigi" uniqKey="Tortola L" first="Luigi" last="Tortola">Luigi Tortola</name><name sortKey="Uribesalgo, Iris" sort="Uribesalgo, Iris" uniqKey="Uribesalgo I" first="Iris" last="Uribesalgo">Iris Uribesalgo</name><name sortKey="Wimmer, Reiner A" sort="Wimmer, Reiner A" uniqKey="Wimmer R" first="Reiner A" last="Wimmer">Reiner A. Wimmer</name><name sortKey="Zhang, Yin" sort="Zhang, Yin" uniqKey="Zhang Y" first="Yin" last="Zhang">Yin Zhang</name><name sortKey="Zuber, Johannes" sort="Zuber, Johannes" uniqKey="Zuber J" first="Johannes" last="Zuber">Johannes Zuber</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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