VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors.
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.
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.|Institute of Experimental Biomedicine, Universitätsklinikum Würzburg, Würzburg, Germany.|Graduate School of Life Science, Universität Würzburg, Würzburg, Germany.
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Röhrig
Institute of Experimental Biomedicine, Universitätsklinikum Würzburg, Würzburg, Germany.
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Vorlová
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.|Institute of Experimental Biomedicine, Universitätsklinikum Würzburg, Würzburg, Germany.|Graduate School of Life Science, Universität Würzburg, Würzburg, Germany.
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Hoffmann
Institute of Pathology, Universität Würzburg, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany.
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Wartenberg
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Escorcia
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.
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Keller
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.
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Tenspolde
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.
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Weigand
Institute of Experimental Biomedicine, Universitätsklinikum Würzburg, Würzburg, Germany.
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Gätzner
Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Manova
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie Universitätsklinikum Charité, Berlin, Germany.
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Penack
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Scheinberg
Institute of Pathology, Universität Würzburg, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany.
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Rosenwald
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.
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Ergün
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada and Hebrew University-Hadassah Medical School, Jerusalem, Israel.
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Granot
Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.|Institute of Experimental Biomedicine, Universitätsklinikum Würzburg, Würzburg, Germany.|Graduate School of Life Science, Universität Würzburg, Würzburg, Germany.
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Henke
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010539:Permeability; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A; D008249:Protein-Lysine 6-Oxidase