TY  - JOUR
A1  - Schütze, Friedrich
A1  - Röhring, Florian
A1  - Vorlová, Sandra
A1  - Gätzner, Sabine
A1  - Kuhn, Anja
A1  - Ergün, Süleyman
A1  - Henke, Erik
T1  - Inhibition of lysyl oxidases improves drug diffusion and increases efficacy of cytotoxic treatment in 3D tumor models
JF  - Scientific Reports
N2  - Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3D in vitro assay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from the in vitro experiments correlated with tumor drug distribution in vivo, and predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases.
KW  - human osteosarcoma xenografts
KW  - factor binding profiles
KW  - open-access database
KW  - vascular normalization
KW  - solid tumors
KW  - transcapillary pressure gradient
KW  - hypoxia inducible factor 1
KW  - breast cancer cells
KW  - beta-aminopropionitrile
KW  - pancreatic cancer
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145109
VL  - 5
IS  - 17576
ER  - 
TY  - JOUR
A1  - Rossow, Leonie
A1  - Veitl, Simona
A1  - Vorlová, Sandra
A1  - Wax, Jacqueline K.
A1  - Kuhn, Anja E.
A1  - Maltzahn, Verena
A1  - Upcin, Berin
A1  - Karl, Franziska
A1  - Hoffmann, Helene
A1  - Gätzner, Sabine
A1  - Kallius, Matthias
A1  - Nandigama, Rajender
A1  - Scheld, Daniela
A1  - Irmak, Ster
A1  - Herterich, Sabine
A1  - Zernecke, Alma
A1  - Ergün, Süleyman
A1  - Henke, Erik
T1  - LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy
JF  - Oncogene
N2  - 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.
KW  - Cancer models
KW  - Cancer therapeutic resistance
KW  - Targeted therapies
KW  - Tumour angiogenesis
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227008
VL  - 37
ER  -