Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition
Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy. Glioma stem cell (GSC) NSC11...
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| Veröffentlicht in: | Clinical cancer research 2013-08, Vol.19 (16), p.4392-4403 |
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| creator | YUJI PIAO JI LIANG HOLMES, Lindsay HENRY, Verlene SULMAN, Erik DE GROOT, John F |
| description | Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy.
Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy. |
| doi_str_mv | 10.1158/1078-0432.CCR-12-1557 |
| format | Article |
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Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-12-1557</identifier><identifier>PMID: 23804423</identifier><identifier>CODEN: CCREF4</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Angiogenesis Inhibitors - pharmacology ; Animals ; Antibodies, Monoclonal, Humanized - pharmacology ; Antineoplastic agents ; Bevacizumab ; Biological and medical sciences ; Cell Line, Tumor ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition - drug effects ; Female ; Gene Expression Profiling ; Glioblastoma - drug therapy ; Glioblastoma - metabolism ; Glioblastoma - mortality ; Glioblastoma - pathology ; Humans ; Medical sciences ; Mice ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Myeloid Cells - immunology ; Myeloid Cells - metabolism ; Neoplasm Invasiveness ; Neovascularization, Pathologic ; Neurology ; Pharmacology. Drug treatments ; Signal Transduction ; Tumors ; Tumors of the nervous system. Phacomatoses ; Vascular Endothelial Growth Factor A - antagonists & inhibitors ; Vascular Endothelial Growth Factor A - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Clinical cancer research, 2013-08, Vol.19 (16), p.4392-4403</ispartof><rights>2014 INIST-CNRS</rights><rights>2013 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-95ece1dfab908bfd05acd4e6aa35d2968ce4f12acb63a2600d397ba3faf8ae0a3</citedby><cites>FETCH-LOGICAL-c386t-95ece1dfab908bfd05acd4e6aa35d2968ce4f12acb63a2600d397ba3faf8ae0a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,3345,27911,27912</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27638226$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23804423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>YUJI PIAO</creatorcontrib><creatorcontrib>JI LIANG</creatorcontrib><creatorcontrib>HOLMES, Lindsay</creatorcontrib><creatorcontrib>HENRY, Verlene</creatorcontrib><creatorcontrib>SULMAN, Erik</creatorcontrib><creatorcontrib>DE GROOT, John F</creatorcontrib><title>Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy.
Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.</description><subject>Angiogenesis Inhibitors - pharmacology</subject><subject>Animals</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Bevacizumab</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Drug Resistance, Neoplasm</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - mortality</subject><subject>Glioblastoma - pathology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Myeloid Cells - immunology</subject><subject>Myeloid Cells - metabolism</subject><subject>Neoplasm Invasiveness</subject><subject>Neovascularization, Pathologic</subject><subject>Neurology</subject><subject>Pharmacology. Drug treatments</subject><subject>Signal Transduction</subject><subject>Tumors</subject><subject>Tumors of the nervous system. Phacomatoses</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtLw0AQgBdRtD5-grIXwUt0X0m3x1JqFRRBqtdlspnQlTzazBbpvzehVU8zh--bgY-xaynupUztgxRjmwij1f1s9p5Ilcg0HR-x0TASrbL0uN9_mTN2TvQlhDRSmFN2prQVxig9YsXUb7ahw4K_IwWK0HjkseXTJobkc7545MsVdrDe8dDwRRXavAKKbQ38mfiUqPUBYm9_h7jiwF-RsPGrXQ0VX3bQUIihbS7ZSQkV4dVhXrCPx_ly9pS8vC2eZ9OXxGubxWSSokdZlJBPhM3LQqTgC4MZgE4LNcmsR1NKBT7PNKhMiEJPxjnoEkoLKEBfsLv93XXXbrZI0dWBPFYVNNhuyUkzWNpY26PpHvVdS9Rh6dZdqKHbOSncENgN8dwQz_WBnVRuKNt7N4cX27zG4s_6LdoDtwcAyENV9hF8oH9unGmrVKZ_AJHBhOI</recordid><startdate>20130815</startdate><enddate>20130815</enddate><creator>YUJI PIAO</creator><creator>JI LIANG</creator><creator>HOLMES, Lindsay</creator><creator>HENRY, Verlene</creator><creator>SULMAN, Erik</creator><creator>DE GROOT, John F</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20130815</creationdate><title>Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition</title><author>YUJI PIAO ; JI LIANG ; HOLMES, Lindsay ; HENRY, Verlene ; SULMAN, Erik ; DE GROOT, John F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-95ece1dfab908bfd05acd4e6aa35d2968ce4f12acb63a2600d397ba3faf8ae0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Animals</topic><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Bevacizumab</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Drug Resistance, Neoplasm</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - mortality</topic><topic>Glioblastoma - pathology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Myeloid Cells - immunology</topic><topic>Myeloid Cells - metabolism</topic><topic>Neoplasm Invasiveness</topic><topic>Neovascularization, Pathologic</topic><topic>Neurology</topic><topic>Pharmacology. Drug treatments</topic><topic>Signal Transduction</topic><topic>Tumors</topic><topic>Tumors of the nervous system. Phacomatoses</topic><topic>Vascular Endothelial Growth Factor A - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>YUJI PIAO</creatorcontrib><creatorcontrib>JI LIANG</creatorcontrib><creatorcontrib>HOLMES, Lindsay</creatorcontrib><creatorcontrib>HENRY, Verlene</creatorcontrib><creatorcontrib>SULMAN, Erik</creatorcontrib><creatorcontrib>DE GROOT, John F</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>YUJI PIAO</au><au>JI LIANG</au><au>HOLMES, Lindsay</au><au>HENRY, Verlene</au><au>SULMAN, Erik</au><au>DE GROOT, John F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2013-08-15</date><risdate>2013</risdate><volume>19</volume><issue>16</issue><spage>4392</spage><epage>4403</epage><pages>4392-4403</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><coden>CCREF4</coden><abstract>Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy.
Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>23804423</pmid><doi>10.1158/1078-0432.CCR-12-1557</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2013-08, Vol.19 (16), p.4392-4403 |
| issn | 1078-0432 1557-3265 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Angiogenesis Inhibitors - pharmacology Animals Antibodies, Monoclonal, Humanized - pharmacology Antineoplastic agents Bevacizumab Biological and medical sciences Cell Line, Tumor Disease Models, Animal Drug Resistance, Neoplasm Epithelial-Mesenchymal Transition - drug effects Female Gene Expression Profiling Glioblastoma - drug therapy Glioblastoma - metabolism Glioblastoma - mortality Glioblastoma - pathology Humans Medical sciences Mice Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Myeloid Cells - immunology Myeloid Cells - metabolism Neoplasm Invasiveness Neovascularization, Pathologic Neurology Pharmacology. Drug treatments Signal Transduction Tumors Tumors of the nervous system. Phacomatoses Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - metabolism Xenograft Model Antitumor Assays |
| title | Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition |
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