Universität zu Köln

Coutelle, O., Schiffmann, L. M., Liwschitz, M., Brunold, M., Goede, V., Hallek, M., Kashkar, H. and Hacker, U. T. (2015). Dual targeting of Angiopoetin-2 and VEGF potentiates effective vascular normalisation without inducing empty basement membrane sleeves in xenograft tumours. Br. J. Cancer, 112 (3). S. 495 - 504. LONDON: NATURE PUBLISHING GROUP. ISSN 1532-1827

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Abstract

Background: Effective vascular normalisation following vascular endothelial growth factor (VEGF) inhibition is associated with endothelial cell regression leaving empty basement membrane sleeves (BMS). These long-lived BMS permit the rapid regrowth of tumour vasculature upon treatment cessation and promote resistance to VEGF-targeting drugs. Previous attempts at removing BMS have failed. Angiopoietin-2 (Ang2) is a vascular destabilizing factor that antagonises normalisation. We hypothesised that Ang2 inhibition could permit vascular normalisation at significantly reduced doses of VEGF inhibition, avoiding excessive vessel regression and the formation of empty BMS. Methods: Mice xenografted with human colorectal cancer cells (LS174T) were treated with low (0.5 mg kg(-1)) or high (5 mg kg(-1)) doses of the VEGF-targeting antibody bevacizumab with or without an Ang2 blocking peptibody L1-10. Tumour growth, BMS formation and normalisation parameters were examined including vessel density, pericyte coverage, adherence junctions, leakiness, perfusion, hypoxia and proliferation. Results: Dual targeting of VEGF and Ang2 achieved effective normalisation at only one-tenth of the dose required with bevacizumab alone. Pericyte coverage, vascular integrity, adherence junctions and perfusion as prerequisites for improved access of chemotherapy were improved without inducing empty BMS that facilitate rapid vascular regrowth. Conclusions: Dual targeting of VEGF and Ang2 can potentiate the effectiveness of VEGF inhibitors and avoid the formation of empty BMS.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Coutelle, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schiffmann, L. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Liwschitz, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunold, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goede, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kashkar, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hacker, U. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-412686
DOI:	10.1038/bjc.2014.629
Journal or Publication Title:	Br. J. Cancer
Volume:	112
Number:	3
Page Range:	S. 495 - 504
Date:	2015
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1532-1827
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language METASTATIC COLORECTAL-CANCER; ANTI-ANGIOGENIC THERAPY; ANTITUMOR-ACTIVITY; ANGIOPOIETIN-2; BEVACIZUMAB; INHIBITION; GROWTH; HYPOXIA; FLUOROURACIL; CHEMOTHERAPY Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41268