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Updated: Apr 6, 2026
High-Resolution Ultrasonography for the Analysis of Orthotopic ATC Tumors in a Genetically Engineered Mouse Model
Published on: October 11, 2022
Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound
Ahmed El Kaffas1, Ali Sadeghi-Naini1, Omar Falou1
1Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Purpose:
It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments.
Methods:
Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively.
Results:
Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R(2) of 0.9 was observed when quantified cell death was correlated with changes in midband fit.
Conclusions:
Results from QUS analysis presented in this study confirm that acute tumor response is linked to a vascular effect following high doses of radiation therapy. Overall, this is in agreement with previous reports suggesting that acute tumor radiation response is regulated by a vascular-driven response. Data also suggest that Sunitinib may enhance tumor radiosensitivity through a vascular remodeling process, and that QUS may be sensitive to changes in tissue properties associated with vascular remodeling. Finally, the work also demonstrates the ability of QUS methods to monitor response to radiation-based vascular strategies.
Insights
Quantitative ultrasound spectroscopy (QUS) reveals that radiation therapy combined with Sunitinib significantly impacts tumor vasculature, enhancing tumor cell death. QUS effectively monitors these vascular-driven responses to radiation therapy.
Area of Science:
- Oncology
- Medical Imaging
- Radiotherapy
Background:
- Tumor vasculature plays a key role in regulating responses to radiation therapy.
- The precise contribution of radiation-induced vascular damage to tumor cell death is not fully understood.
- Quantitative ultrasound spectroscopy (QUS) offers a method to investigate acute tumor responses.
Purpose of the Study:
- To utilize quantitative ultrasound spectroscopy (QUS) to investigate the acute vascular responses of tumors to radiation therapy.
- To assess the impact of combining radiation with vascular-modulating agents on tumor response.
- To correlate QUS parameters with established measures of tumor cell death, oxygenation, and vasculature.
Main Methods:
- Tumor xenografts (MDA-MB-231) were subjected to single radiation doses (2 or 8 Gy) alone or with Sunitinib (anti-angiogenic) or basic fibroblast growth factor (endothelial radioprotector).
- Quantitative ultrasound spectroscopy (QUS) parameters (midband fit, slope, 0-MHz intercept) were derived from pre- and post-treatment ultrasound backscatter power spectra.
- Tumor sections were analyzed using in situ end labeling, carbonic anhydrase 9, and cluster of differentiation 31 staining to assess cell death, oxygenation, and vasculature.
Main Results:
- QUS showed significant increases in the midband fit parameter for tumors treated with 8 Gy radiation plus Sunitinib (5.4 ± 0.5 dBr) and 2 Gy plus Sunitinib (3.2 ± 0.3 dBr).
- Radiation alone at 8 Gy resulted in a significant midband fit increase (4.4 ± 0.3 dBr), while basic fibroblast growth factor minimized tumor response.
- Immunohistochemical analysis supported QUS findings, with a strong correlation (R² = 0.9) observed between quantified cell death and midband fit changes.
Conclusions:
- Acute tumor response to high-dose radiation therapy is significantly linked to vascular effects, as confirmed by QUS analysis.
- Sunitinib may enhance tumor radiosensitivity via vascular remodeling, and QUS is sensitive to these associated tissue property changes.
- QUS methods are demonstrated to be effective in monitoring responses to radiation-based vascular treatment strategies.
