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  - 
TY  - JOUR
A1  - Ascheid, David
A1  - Baumann, Magdalena
A1  - Funke, Caroline
A1  - Volz, Julia
A1  - Pinnecker, Jürgen
A1  - Friedrich, Mike
A1  - Höhn, Marie
A1  - Nandigama, Rajender
A1  - Ergün, Süleyman
A1  - Nieswandt, Bernhard
A1  - Heinze, Katrin G.
A1  - Henke, Erik
T1  - Image-based modeling of vascular organization to evaluate anti-angiogenic therapy
JF  - Biology Direct
N2  - In tumor therapy anti-angiogenic approaches have the potential to increase the efficacy of a wide variety of subsequently or co-administered agents, possibly by improving or normalizing the defective tumor vasculature. Successful implementation of the concept of vascular normalization under anti-angiogenic therapy, however, mandates a detailed understanding of key characteristics and a respective scoring metric that defines an improved vasculature and thus a successful attempt. Here, we show that beyond commonly used parameters such as vessel patency and maturation, anti-angiogenic approaches largely benefit if the complex vascular network with its vessel interconnections is both qualitatively and quantitatively assessed. To gain such deeper insight the organization of vascular networks, we introduce a multi-parametric evaluation of high-resolution angiographic images based on light-sheet fluorescence microscopy images of tumors. We first could pinpoint key correlations between vessel length, straightness and diameter to describe the regular, functional and organized structure observed under physiological conditions. We found that vascular networks from experimental tumors diverted from those in healthy organs, demonstrating the dysfunctionality of the tumor vasculature not only on the level of the individual vessel but also in terms of inadequate organization into larger structures. These parameters proofed effective in scoring the degree of disorganization in different tumor entities, and more importantly in grading a potential reversal under treatment with therapeutic agents. The presented vascular network analysis will support vascular normalization assessment and future optimization of anti-angiogenic therapy.
KW  - vascular structure
KW  - cancer
KW  - tumor microenvironment
KW  - optical clearing
KW  - light sheet fluorescence microscopy
KW  - 3D image analysis
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357242
VL  - 18
ER  -