Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
Identifieur interne : 000A69 ( Main/Merge ); précédent : 000A68; suivant : 000A70Apelin 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></record>Pour manipuler ce document sous Unix (Dilib)
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