Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors

Tozer, Gillian M, Akerman, Simon, Cross, Neil A, Barber, Paul R, Bjorndahl, Meit A, Greco, Olga, Harris, Sheila, Hill, Sally A, Honness, Davina J, Ireson, Christopher R, Pettyjohn, Katie L, Prise, Vivien E, Reyes Aldasoro, Constantino C, Ruhrberg, Christina, Shima, David T and Kanthou, Chryso (2008) Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors. Cancer Research, 68 (7). pp. 2301-2311. ISSN 0008-5472

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Abstract

Tubulin-binding vascular-disrupting agents (VDA) are currently in clinical trials for cancer therapy but the factors that influence tumor susceptibility to these agents are poorly understood. We evaluated the consequences of modifying tumor vascular morphology and function on vascular and therapeutic response to combretastatin-A4 3-O-phosphate (CA-4-P), which was chosen as a model VDA. Mouse fibrosarcoma cell lines that are capable of expressing all vascular endothelial growth factor (VEGF) isoforms (control) or only single isoforms of VEGF (VEGF120, VEGF164, or VEGF188) were developed under endogenous VEGF promoter control. Once tumors were established, VEGF isoform expression did not affect growth or blood flow rate. However, VEGF188 was uniquely associated with tumor vascular maturity, resistance to hemorrhage, and resistance to CA-4-P. Pericyte staining was much greater in VEGF188 and control tumors than in VEGF120 and VEGF164 tumors. Vascular volume was highest in VEGF120 and control tumors (CD31 staining) but total vascular length was highest in VEGF188 tumors, reflecting very narrow vessels forming complex vascular networks. I.v. administered 40 kDa FITC-dextran leaked slowly from the vasculature of VEGF188 tumors compared with VEGF120 tumors. Intravital microscopy measurements of vascular length and RBC velocity showed that CA-4-P produced significantly more vascular damage in VEGF120 and VEGF164 tumors than in VEGF188 and control tumors. Importantly, this translated into a similar differential in therapeutic response, as determined by tumor growth delay. Results imply differences in signaling pathways between VEGF isoforms and suggest that VEGF isoforms might be useful in vascular-disrupting cancer therapy to predict tumor susceptibility to VDAs.

Item Type: Article
Additional Information: This is an article that reflects world-leading research in Cancer Research with very significant methodologies and original results. The quality and impact on the field of Oncology, Medicine and Biology can be assessed by the 36 citations it has received between 2008 and 2011. I had a strong contribution towards the design of the studies and the quantitative analysis between the different tumour lines. Without the use of quantitative image analysis algorithms, the processing of these images would have been a qualitative assessment by a viewer and therefore subject ot subjectivity and intra- and inter-observer variability.
Schools and Departments: School of Engineering and Informatics > Engineering and Design
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 20:06
Last Modified: 30 Mar 2012 13:43
URI: http://sro.sussex.ac.uk/id/eprint/24084
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