Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy
Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast ca...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716304417 |
| _version_ | 1828769092728782848 |
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| author | Laura Pisarsky Ruben Bill Ernesta Fagiani Sarah Dimeloe Ryan William Goosen Jörg Hagmann Christoph Hess Gerhard Christofori |
| author_facet | Laura Pisarsky Ruben Bill Ernesta Fagiani Sarah Dimeloe Ryan William Goosen Jörg Hagmann Christoph Hess Gerhard Christofori |
| author_sort | Laura Pisarsky |
| collection | DOAJ |
| description | Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients. |
| first_indexed | 2024-12-11T13:42:20Z |
| format | Article |
| id | doaj.art-2e1f3cdad32948ae82dae8837ddcdd50 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T13:42:20Z |
| publishDate | 2016-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2e1f3cdad32948ae82dae8837ddcdd502022-12-22T01:04:43ZengElsevierCell Reports2211-12472016-05-011561161117410.1016/j.celrep.2016.04.028Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic TherapyLaura Pisarsky0Ruben Bill1Ernesta Fagiani2Sarah Dimeloe3Ryan William Goosen4Jörg Hagmann5Christoph Hess6Gerhard Christofori7Department of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandDespite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.http://www.sciencedirect.com/science/article/pii/S2211124716304417 |
| spellingShingle | Laura Pisarsky Ruben Bill Ernesta Fagiani Sarah Dimeloe Ryan William Goosen Jörg Hagmann Christoph Hess Gerhard Christofori Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy Cell Reports |
| title | Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy |
| title_full | Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy |
| title_fullStr | Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy |
| title_full_unstemmed | Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy |
| title_short | Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy |
| title_sort | targeting metabolic symbiosis to overcome resistance to anti angiogenic therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716304417 |
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