VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors
| Autor: | Andreas Rosenwald, Sandra Vorlová, Florian Röhrig, Erik Henke, David A. Scheinberg, H. Hoffmann, Sabine Gätzner, Isabel Weigand, Zvi Granot, Martin Wartenberg, Olaf Penack, Freddy E. Escorcia, Süleyman Ergün, S Keller, M Tenspolde, Katia Manova |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Cancer Research medicine.medical_treatment Biology Pharmacology Molecular oncology Models Biological Permeability Extracellular matrix Protein-Lysine 6-Oxidase 03 medical and health sciences Mice Growth factor receptor Cell Line Tumor Neoplasms Genetics medicine Animals Humans Molecular Targeted Therapy Molecular Biology Growth factor Cancer Antibodies Monoclonal Sarcoma medicine.disease Xenograft Model Antitumor Assays Extracellular Matrix Vascular endothelial growth factor A Disease Models Animal 030104 developmental biology Drug Resistance Neoplasm Drug delivery Female Original Article |
| Zdroj: | Oncogene Röhrig, F; Vorlová, S; Hoffmann, H; Wartenberg, Martin; Escorcia, F E; Keller, S; Tenspolde, M; Weigand, I; Gätzner, S; Manova, K; Penack, O; Scheinberg, D A; Rosenwald, A; Ergün, S; Granot, Z; Henke, E (2016). VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors. Oncogene, 36(1), pp. 1-12. Nature Publishing Group 10.1038/onc.2016.182 |
| ISSN: | 1476-5594 |
| DOI: | 10.1038/onc.2016.182 |
| Popis: | The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.Oncogene advance online publication, 6 June 2016; doi:10.1038/onc.2016.182. |
| Databáze: | OpenAIRE |
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