Radiation effects on tumour microcirculation assessed by high-frequency power doppler micro-ultrasound imaging in mice

5768 Recent evidence suggests that radiation may have very significant effects on tumour vasculature in addition to damaging the DNA inside tumour cells. We have previously demonstrated that with large doses (>8 Gy) that there can be large macroscopic areas of apoptotic death that develop in response to therapy. In this study we test the hypothesis that large doses of radiation (8Gy) have significant effects on blood flow and tumour microvasculature and that these effects can be detected and measured non-invasively by high-frequency power Doppler ultrasound vascular imaging.
 Human PC3 prostate cancer xenograft-bearing SCID mice were exposed to 8 Gy irradiation with 160 kVp X-rays at a dose rate of 200 cGy/minute given in one fraction. Four animals were irradiated and four animals served as sham controls. Tumours were assessed before any treatment and 24 hours after the administration of radiation by high-frequency spectroscopic ultrasound imaging for cell death detection and then with power Doppler imaging at 20 MHz frequency to image blood flow. A VisualSonics VEVO-770 RF enabled high-frequency ultrasound device was used with a RMV-710B probe to acquire three-dimensional ultrasound data sets were collected. Ultrasound data sets were analyzed using custom written software and standard two-dimensional image processing tools. Tumours were subsequently removed after animal sacrifice for histological and immunohistochemistry-based analyses. Representative tumour sections were haematoxylin and eosin stained, TUNEL stained for apoptotic cell death and CD31 stained for endothelial distributions.
 Three-dimensional power Doppler analyses indicated heterogeneous distributions within tumours before and after treatment. Results with radiation treatments indicated significant changes between vascular imaging parameters before and after 8Gy radiation doses. Specifically, power Doppler estimated % vascularity dropped within 0.18 to 0.35 of original measurements. Analyses of vascular signals indicated that all detected vessel sizes were evenly affected by the radiation treatments. Additionally, within the tumours the number of power Doppler signals dropped with radiation by 25 to 50%. Preliminary histological analyses indicate that radiation effects were linked to apoptotic perturbations of tumour vasculature endothelial cells. This is consistent with an approximate 10 dB increase in total ultrasound backscatter power at 20 MHz.
 This work indicated that 8 Gy doses had significant effects on tumour vasculature as assessed by high-frequency power Doppler. Experimental evidence suggests that this vascular response may be linked to endothelial cell apoptosis ultimately leading to tumour cell death as demonstrated by histology and indicated by the increase in backscattered ultrasound power.

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