LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy
| Autor: | Sandra Vorlová, Simona Veitl, Anja E Kuhn, Ster Irmak, Berin Upcin, Sabine Herterich, Matthias Kallius, Leonie Rossow, Daniela Scheld, Jacqueline K. Wax, Franziska Karl, Verena Maltzahn, Erik Henke, H. Hoffmann, Sabine Gätzner, Süleyman Ergün, Rajender Nandigama, Alma Zernecke |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Angiogenesis Intrinsic resistance medicine.medical_treatment Drug resistance Biology Article Protein-Lysine 6-Oxidase 03 medical and health sciences Mice Cell Line Tumor Genetics medicine Animals Humans ddc:610 Molecular Biology chemistry.chemical_classification Chemotherapy Extracellular Matrix Proteins Hypoxia (medical) Extracellular Matrix Mice Inbred C57BL 030104 developmental biology Enzyme chemistry Cell culture Drug Resistance Neoplasm Cancer research Female Collagen medicine.symptom Tissue stiffness Signal Transduction |
| Zdroj: | Oncogene |
| DOI: | 10.1038/s41388-018-0320-2 |
| Popis: | The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|