Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression
Abstract Purpose: VEGF-targeted therapies have modest efficacy in cancerpatients, butacquiredresistance iscommon. Themechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Artículo |
| Lenguaje: | inglés |
| Publicado: |
2017
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| Acceso en línea: | http://eprints.uanl.mx/17479/1/308.pdf |
| _version_ | 1824414908763078656 |
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| author | Dalton, Heather J. Pradeep, Sunila McGuire, Michael Hailemichael, Yared MA, Shaolin Lyons, Yasmin Armaiz Pena, Guillermo N. Previs, Rebecca A. Hansen, Jean Marie Rupaimoole, Rajesha González Villasana, Vianey Cho, Min Soon Wu, Sherry Y. Mangala, Lingegowda S. Jennings, Nicholas B. Hu, Wei Langley, Robert Mu, Hong Andreeff, Michael Bar Eli, Menashe Overwijk, Willem Ram, Prahlad Lopez Berestein, Gabriel Coleman, Robert L. Sood, Anil K. |
| author_facet | Dalton, Heather J. Pradeep, Sunila McGuire, Michael Hailemichael, Yared MA, Shaolin Lyons, Yasmin Armaiz Pena, Guillermo N. Previs, Rebecca A. Hansen, Jean Marie Rupaimoole, Rajesha González Villasana, Vianey Cho, Min Soon Wu, Sherry Y. Mangala, Lingegowda S. Jennings, Nicholas B. Hu, Wei Langley, Robert Mu, Hong Andreeff, Michael Bar Eli, Menashe Overwijk, Willem Ram, Prahlad Lopez Berestein, Gabriel Coleman, Robert L. Sood, Anil K. |
| author_sort | Dalton, Heather J. |
| collection | Repositorio Institucional |
| description | Abstract
Purpose: VEGF-targeted therapies have modest efficacy in cancerpatients, butacquiredresistance iscommon. Themechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized roleofmacrophagesinsuchresistance.Macrophageswereactively recruited to the tumor microenvironment and were responsible
for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophagedeficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combinationapproachesforovarianandothercancers. ClinCancerRes; 23(22); 7034–46. �2017 AACR. |
| format | Article |
| id | eprints-17479 |
| institution | UANL |
| language | English |
| publishDate | 2017 |
| record_format | eprints |
| spelling | eprints-174792022-03-23T20:19:31Z http://eprints.uanl.mx/17479/ Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression Dalton, Heather J. Pradeep, Sunila McGuire, Michael Hailemichael, Yared MA, Shaolin Lyons, Yasmin Armaiz Pena, Guillermo N. Previs, Rebecca A. Hansen, Jean Marie Rupaimoole, Rajesha González Villasana, Vianey Cho, Min Soon Wu, Sherry Y. Mangala, Lingegowda S. Jennings, Nicholas B. Hu, Wei Langley, Robert Mu, Hong Andreeff, Michael Bar Eli, Menashe Overwijk, Willem Ram, Prahlad Lopez Berestein, Gabriel Coleman, Robert L. Sood, Anil K. Abstract Purpose: VEGF-targeted therapies have modest efficacy in cancerpatients, butacquiredresistance iscommon. Themechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized roleofmacrophagesinsuchresistance.Macrophageswereactively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophagedeficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combinationapproachesforovarianandothercancers. ClinCancerRes; 23(22); 7034–46. �2017 AACR. 2017-11-15 Article PeerReviewed text en cc_by_nc_nd http://eprints.uanl.mx/17479/1/308.pdf http://eprints.uanl.mx/17479/1.haspreviewThumbnailVersion/308.pdf Dalton, Heather J. y Pradeep, Sunila y McGuire, Michael y Hailemichael, Yared y MA, Shaolin y Lyons, Yasmin y Armaiz Pena, Guillermo N. y Previs, Rebecca A. y Hansen, Jean Marie y Rupaimoole, Rajesha y González Villasana, Vianey y Cho, Min Soon y Wu, Sherry Y. y Mangala, Lingegowda S. y Jennings, Nicholas B. y Hu, Wei y Langley, Robert y Mu, Hong y Andreeff, Michael y Bar Eli, Menashe y Overwijk, Willem y Ram, Prahlad y Lopez Berestein, Gabriel y Coleman, Robert L. y Sood, Anil K. (2017) Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. Clinical Cancer Research, 23 (22). pp. 7034-7046. ISSN 1078-0432 http://doi.org/10.1158/1078-0432.CCR-17-0647 doi:10.1158/1078-0432.CCR-17-0647 |
| spellingShingle | Dalton, Heather J. Pradeep, Sunila McGuire, Michael Hailemichael, Yared MA, Shaolin Lyons, Yasmin Armaiz Pena, Guillermo N. Previs, Rebecca A. Hansen, Jean Marie Rupaimoole, Rajesha González Villasana, Vianey Cho, Min Soon Wu, Sherry Y. Mangala, Lingegowda S. Jennings, Nicholas B. Hu, Wei Langley, Robert Mu, Hong Andreeff, Michael Bar Eli, Menashe Overwijk, Willem Ram, Prahlad Lopez Berestein, Gabriel Coleman, Robert L. Sood, Anil K. Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression |
| thumbnail | https://rediab.uanl.mx/themes/sandal5/images/online.png |
| title | Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression |
| title_full | Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression |
| title_fullStr | Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression |
| title_full_unstemmed | Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression |
| title_short | Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression |
| title_sort | macrophages facilitate resistance to anti vegf therapy by altered vegfr expression |
| url | http://eprints.uanl.mx/17479/1/308.pdf |
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