Abstract 4121: Differences in optoacoustic signal reflect different characteristics of the vasculature and response to antiangiogenic therapy in breast cancer models
Authors: Quiros-Gonzalez Isabel , Tomaszewski Michal , Ansel-Bollepalli Laura , Aikten Sarah J. , Gill Michael , Bohndiek Sarah E. 
Published: August 2018

Abstract
Optoacoustic imaging has the potential to monitor tumour neo-vascularization, essential for disease progression and also a target for therapy. While promising in some settings, anti-angiogenic therapy has yet to fulfil its promise and mechanisms of resistance are poorly understood. In breast cancer, for example, resistance has been linked to hormonal status, oxygen consumption and alternative mechanisms of neo-vasculogenesis, including vascular mimicry (VM). Here, we use two mouse xenograft models: estrogen-dependent MCF-7 and estrogen independent MDA-MB-231. We analyse their characteristics in vivo using Multispectral optoacoustic tomography (MSOT) to detect oxy- and deoxy- haemoglobin (Hb) during tumour growth. We also analysed their histological and biochemical characteristics for blood vessel density (CD31) and maturity (aSMA, PAS staining), tumour hypoxia (CAIX), angiogenesis, inflammation and VM. Anti-angiogenic therapy response was also tested using Bevacizumab (BV, 10 mg/Kg) in two cohorts. While MSOT reveals similar blood content in both tumours, estrogen-dependent MCF-7 tumours show higher blood oxygenation than estrogen-independent MDA-MB-231 (55.8±7.5 % vs. 45.6±5.1%, p=0.0008) with values similar to healthy tissue (55.8±7.5 % vs. 57.8±5.3%, p=0.917). Ex vivo histological analysis shows that while MDA-MB-231 tumours are more hypoxic compared to MCF-7, they have a higher blood vessel density, however, the vasculature of MCF-7 tumours is more mature (vessel wall thickness and aSMA coverage). Based on molecular biomarkers, MCF-7 presents a more pro-inflammatory endothelial-like response, marked by an increase of vascular endothelial growth factor (p&lt;0.0001) of host origin (mVEGF), macrophage Nitric Oxide Sinthase (iNOS) and circulating NO, a mediator in inflammation and endothelial homeostasis (p=0.0031). VE-Cadherin of human origin is detectable in MDA-MB-231 tumours, which present CD31-absent blood vessels; together, these findings indicate presence of VM in MDA-MB-231 tumours. Interestingly, these 2 biological profiles respond differently to the anti-angiogenic drug BV: we observed a partial response in MDA-MB-231 tumours (CR=2/22, PR=3/22), but no effect in tumour size or survival was observed in MCF-7 tumours. While no change was observed in mVEGF upon BV treatment in any cohort, changes in optoacoustic signal of total Hb were observed in the MDA-MB-231 tumours after treatment. In conclusion, optoacoustic imaging delineates the vascular function of the blood vessel networks generated by angiogenesis and vascular mimicry respectively in our estrogen-dependent and estrogen-independent breast cancer xenografts. This study highlights the potential application of this technique in monitoring tumour vasculature development and in the future could be used to assess response to therapy.
Citation Format: Isabel Quiros-Gonzalez, Michal Tomaszewski, Laura Ansel-Bollepalli, Sarah J. Aikten, Michael Gill, Sarah E. Bohndiek. Differences in optoacoustic signal reflect different characteristics of the vasculature and response to antiangiogenic therapy in breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4121.