A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology
Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF,...
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| Veröffentlicht in: | PloS one 2015-04, Vol.10 (4), p.e0125697-e0125697 |
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| creator | Tate, Courtney M Mc Entire, Jacquelyn Pallini, Roberto Vakana, Eliza Wyss, Lisa Blosser, Wayne Ricci-Vitiani, Lucia D'Alessandris, Quintino Giorgio Morgante, Liliana Giannetti, Stefano Larocca, Luigi Maria Todaro, Matilde Benfante, Antonina Colorito, Maria Luisa Stassi, Giorgio De Maria, Ruggero Rowlinson, Scott Stancato, Louis |
| description | Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis. |
| doi_str_mv | 10.1371/journal.pone.0125697 |
| format | Article |
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Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0125697</identifier><identifier>PMID: 25919028</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adipose Tissue - cytology ; AKT protein ; Angiogenesis ; Animals ; Bone morphogenetic protein 7 ; Bone Morphogenetic Protein 7 - pharmacology ; Bone Morphogenetic Protein 7 - therapeutic use ; Cancer treatment ; Cell activation ; Cell culture ; Cell Death - drug effects ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell Proliferation - drug effects ; Cells (Biology) ; Collagen - pharmacology ; Cords ; Drug Combinations ; Endothelial cells ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Endothelium ; Extracellular signal-regulated kinase ; Fibroblast growth factor ; Fibroblast growth factor 2 ; Fibroblast Growth Factor 2 - metabolism ; Fibroblast growth factor receptor 1 ; Glioblastoma ; Glioblastoma - blood supply ; Growth factors ; Hemoglobin ; Hemoglobins ; Human Umbilical Vein Endothelial Cells - drug effects ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; Laminin - pharmacology ; Male ; Mice, Nude ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - pathology ; Neovascularization, Physiologic - drug effects ; Plugs ; Pretreatment ; Proteins ; Proteoglycans - pharmacology ; Receptor, Fibroblast Growth Factor, Type 1 - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Smad protein ; Smad Proteins - metabolism ; Smad4 protein ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - metabolism ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0125697-e0125697</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Tate et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Tate et al 2015 Tate et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-33926bb884687d35830f852488f77a0222c6581f7992f0d7a9495c6af0d20ddf3</citedby><cites>FETCH-LOGICAL-c692t-33926bb884687d35830f852488f77a0222c6581f7992f0d7a9495c6af0d20ddf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412825/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412825/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25919028$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ribatti, Domenico</contributor><creatorcontrib>Tate, Courtney M</creatorcontrib><creatorcontrib>Mc Entire, Jacquelyn</creatorcontrib><creatorcontrib>Pallini, Roberto</creatorcontrib><creatorcontrib>Vakana, Eliza</creatorcontrib><creatorcontrib>Wyss, Lisa</creatorcontrib><creatorcontrib>Blosser, Wayne</creatorcontrib><creatorcontrib>Ricci-Vitiani, Lucia</creatorcontrib><creatorcontrib>D'Alessandris, Quintino Giorgio</creatorcontrib><creatorcontrib>Morgante, Liliana</creatorcontrib><creatorcontrib>Giannetti, Stefano</creatorcontrib><creatorcontrib>Larocca, Luigi Maria</creatorcontrib><creatorcontrib>Todaro, Matilde</creatorcontrib><creatorcontrib>Benfante, Antonina</creatorcontrib><creatorcontrib>Colorito, Maria Luisa</creatorcontrib><creatorcontrib>Stassi, Giorgio</creatorcontrib><creatorcontrib>De Maria, Ruggero</creatorcontrib><creatorcontrib>Rowlinson, Scott</creatorcontrib><creatorcontrib>Stancato, Louis</creatorcontrib><title>A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.</description><subject>Adipose Tissue - cytology</subject><subject>AKT protein</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Bone morphogenetic protein 7</subject><subject>Bone Morphogenetic Protein 7 - pharmacology</subject><subject>Bone Morphogenetic Protein 7 - therapeutic use</subject><subject>Cancer treatment</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell Death - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells (Biology)</subject><subject>Collagen - pharmacology</subject><subject>Cords</subject><subject>Drug Combinations</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelium</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fibroblast growth factor</subject><subject>Fibroblast growth factor 2</subject><subject>Fibroblast Growth Factor 2 - metabolism</subject><subject>Fibroblast growth factor receptor 1</subject><subject>Glioblastoma</subject><subject>Glioblastoma - blood supply</subject><subject>Growth factors</subject><subject>Hemoglobin</subject><subject>Hemoglobins</subject><subject>Human Umbilical Vein Endothelial Cells - drug effects</subject><subject>Human Umbilical Vein Endothelial Cells - metabolism</subject><subject>Humans</subject><subject>Laminin - pharmacology</subject><subject>Male</subject><subject>Mice, Nude</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Neovascularization, Physiologic - drug effects</subject><subject>Plugs</subject><subject>Pretreatment</subject><subject>Proteins</subject><subject>Proteoglycans - pharmacology</subject><subject>Receptor, Fibroblast Growth Factor, Type 1 - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Smad protein</subject><subject>Smad Proteins - metabolism</subject><subject>Smad4 protein</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1FvFCEQxzdGY2v1GxglMTH6cCew7C68mFzPqpe0qdF6r4Rd2F0aDk5gG_vt5bxtc2v6YHgAht_8hxmYLHuJ4BzlFfpw7QZvhZlvnVVziHBRsupRdoxYjmclhvnjg_VR9iyEawiLnJbl0-wIFwwxiOlxNizA6cW3CqyF18JGsLK9rnUM4GrYOA8WttOuU1YFHdIZWOvoHRBW7jc3DsTeu6HrwSftVRPBhZODEVE7C1wLzqx0sVdGCwOWyhhwqp1x3e3z7EkrTFAvxvkk-_n57Gr5dXZ--WW1XJzPmpLhOMtzhsu6ppSUtJJ5QXPY0gITStuqEhBj3JQFRW3FGG6hrAQjrGhKkdYYStnmJ9nrve7WuMDHigWOSgoTCQuSiNWekE5c863XG-FvuROa_zU433Hho26M4gwhKZo0UhSiEKGsZjVFtCa0qQspktbHMdpQb5RslI1emIno9MTqnnfuhhOCMMVFEng3Cnj3a1Ah8o0OTaqbsMoNu3tXFWUElTChb_5BH85upDqREtC2dSlusxPlC4JTCrSELFHzB6g0pNroJn2vVif7xOH9xCExUf2OnRhC4Ksf3_-fvVxP2bcHbK-EiX1wZth9pzAFyR5svAvBq_a-yAjyXXfcVYPvuoOP3ZHcXh0-0L3TXTvkfwA1RAiK</recordid><startdate>20150428</startdate><enddate>20150428</enddate><creator>Tate, Courtney M</creator><creator>Mc Entire, Jacquelyn</creator><creator>Pallini, Roberto</creator><creator>Vakana, Eliza</creator><creator>Wyss, Lisa</creator><creator>Blosser, Wayne</creator><creator>Ricci-Vitiani, Lucia</creator><creator>D'Alessandris, Quintino Giorgio</creator><creator>Morgante, Liliana</creator><creator>Giannetti, Stefano</creator><creator>Larocca, Luigi Maria</creator><creator>Todaro, Matilde</creator><creator>Benfante, Antonina</creator><creator>Colorito, Maria Luisa</creator><creator>Stassi, Giorgio</creator><creator>De Maria, Ruggero</creator><creator>Rowlinson, Scott</creator><creator>Stancato, Louis</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150428</creationdate><title>A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology</title><author>Tate, Courtney M ; Mc Entire, Jacquelyn ; Pallini, Roberto ; Vakana, Eliza ; Wyss, Lisa ; Blosser, Wayne ; Ricci-Vitiani, Lucia ; D'Alessandris, Quintino Giorgio ; Morgante, Liliana ; Giannetti, Stefano ; Larocca, Luigi Maria ; Todaro, Matilde ; Benfante, Antonina ; Colorito, Maria Luisa ; Stassi, Giorgio ; De Maria, Ruggero ; Rowlinson, Scott ; Stancato, Louis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-33926bb884687d35830f852488f77a0222c6581f7992f0d7a9495c6af0d20ddf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adipose Tissue - cytology</topic><topic>AKT protein</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Bone morphogenetic protein 7</topic><topic>Bone Morphogenetic Protein 7 - pharmacology</topic><topic>Bone Morphogenetic Protein 7 - therapeutic use</topic><topic>Cancer treatment</topic><topic>Cell activation</topic><topic>Cell culture</topic><topic>Cell Death - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells (Biology)</topic><topic>Collagen - pharmacology</topic><topic>Cords</topic><topic>Drug Combinations</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelium</topic><topic>Extracellular signal-regulated kinase</topic><topic>Fibroblast growth factor</topic><topic>Fibroblast growth factor 2</topic><topic>Fibroblast Growth Factor 2 - metabolism</topic><topic>Fibroblast growth factor receptor 1</topic><topic>Glioblastoma</topic><topic>Glioblastoma - 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metabolism</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tate, Courtney M</creatorcontrib><creatorcontrib>Mc Entire, Jacquelyn</creatorcontrib><creatorcontrib>Pallini, Roberto</creatorcontrib><creatorcontrib>Vakana, Eliza</creatorcontrib><creatorcontrib>Wyss, Lisa</creatorcontrib><creatorcontrib>Blosser, Wayne</creatorcontrib><creatorcontrib>Ricci-Vitiani, Lucia</creatorcontrib><creatorcontrib>D'Alessandris, Quintino Giorgio</creatorcontrib><creatorcontrib>Morgante, Liliana</creatorcontrib><creatorcontrib>Giannetti, Stefano</creatorcontrib><creatorcontrib>Larocca, Luigi Maria</creatorcontrib><creatorcontrib>Todaro, Matilde</creatorcontrib><creatorcontrib>Benfante, Antonina</creatorcontrib><creatorcontrib>Colorito, Maria Luisa</creatorcontrib><creatorcontrib>Stassi, Giorgio</creatorcontrib><creatorcontrib>De Maria, Ruggero</creatorcontrib><creatorcontrib>Rowlinson, Scott</creatorcontrib><creatorcontrib>Stancato, Louis</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tate, Courtney M</au><au>Mc Entire, Jacquelyn</au><au>Pallini, Roberto</au><au>Vakana, Eliza</au><au>Wyss, Lisa</au><au>Blosser, Wayne</au><au>Ricci-Vitiani, Lucia</au><au>D'Alessandris, Quintino Giorgio</au><au>Morgante, Liliana</au><au>Giannetti, Stefano</au><au>Larocca, Luigi Maria</au><au>Todaro, Matilde</au><au>Benfante, Antonina</au><au>Colorito, Maria Luisa</au><au>Stassi, Giorgio</au><au>De Maria, Ruggero</au><au>Rowlinson, Scott</au><au>Stancato, Louis</au><au>Ribatti, Domenico</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-28</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0125697</spage><epage>e0125697</epage><pages>e0125697-e0125697</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25919028</pmid><doi>10.1371/journal.pone.0125697</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-04, Vol.10 (4), p.e0125697-e0125697 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1680495054 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adipose Tissue - cytology AKT protein Angiogenesis Animals Bone morphogenetic protein 7 Bone Morphogenetic Protein 7 - pharmacology Bone Morphogenetic Protein 7 - therapeutic use Cancer treatment Cell activation Cell culture Cell Death - drug effects Cell Line, Tumor Cell migration Cell Movement - drug effects Cell Proliferation - drug effects Cells (Biology) Collagen - pharmacology Cords Drug Combinations Endothelial cells Endothelial Cells - drug effects Endothelial Cells - metabolism Endothelium Extracellular signal-regulated kinase Fibroblast growth factor Fibroblast growth factor 2 Fibroblast Growth Factor 2 - metabolism Fibroblast growth factor receptor 1 Glioblastoma Glioblastoma - blood supply Growth factors Hemoglobin Hemoglobins Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Humans Laminin - pharmacology Male Mice, Nude Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - pathology Neovascularization, Physiologic - drug effects Plugs Pretreatment Proteins Proteoglycans - pharmacology Receptor, Fibroblast Growth Factor, Type 1 - metabolism Signal transduction Signal Transduction - drug effects Signaling Smad protein Smad Proteins - metabolism Smad4 protein Tumors Vascular endothelial growth factor Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor Receptor-2 - metabolism Xenograft Model Antitumor Assays Xenografts |
| title | A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology |
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