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.
Bibliographical noteFunding Information:
We thank Robert Benezra (Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center) for helpful discussion; Thomas Jarchau (Institute for clinical Biochemistry and Pathobiochemistry, Univeritätsklinikum Würzburg) for a thorough correction of the manuscript; and Afshar Barlas, Mesruh Turkekul (Molecular Cytology Core facility, Memorial Sloan-Kettering Cancer Center) and Oliver Reinhardt (Biology Master Course, Universität Würzburg) for help with experiments. Funding was provided by the Deutsche Forschungsgemeinschaft (DFG Grant Nos. HE3565/1-1, HE3565/2-1 and HE3565/3-1 to EH).
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