Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response

• Published in: Radiation oncology (London, England) Vol. 13; no. 1; pp. 104 - 11
• Main Authors: Zarghami, Niloufar, Murrell, Donna H., Jensen, Michael D., Dick, Frederick A., Chambers, Ann F., Foster, Paula J., Wong, Eugene
• Format: Journal Article
• Language: English
• Published: London BioMed Central 01.06.2018; BioMed Central Ltd; BMC
• Subjects: Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Brain - diagnostic imaging; Brain - metabolism; Brain - radiation effects; Brain cancer; Brain damage; Brain metastases; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - radiotherapy; Brain Neoplasms - secondary; Brain tumors; Breast cancer; Breast Neoplasms - pathology; Cancer; Cancer metastasis; Cancer Research; Cancer therapies; Care and treatment; Cell cycle; Cell Cycle - radiation effects; Cell density; Cell Line, Tumor; Cell size; Computed tomography; Correlation analysis; Cranial Irradiation - methods; Cytokinesis; Density; Deoxyribonucleic acid; Development and progression; Disease control; Disease Models, Animal; Dissection; DNA; DNA biosynthesis; DNA Breaks, Double-Stranded - radiation effects; DNA damage; DNA double-strand breaks; Dose-Response Relationship, Radiation; Drug dosages; Female; Fluorescence; Histology; Histones - metabolism; Histones - radiation effects; Humans; Imaging; Immunohistochemistry; Internet; Irradiation; Longitudinal Studies; Magnetic resonance imaging; Medical imaging; Metastases; Metastasis; Mice; Mice, Nude; Neuroimaging; NMR; Nuclear magnetic resonance; Oncology; Parenchyma; Permeability; Phosphorylation; Phosphorylation - radiation effects; Radiation Biology and Molecular Radiation Oncology; Radiation damage; Radiation dosage; Radiation dose-response; Radiation effects; Radiation therapy; Radiation Tolerance - physiology; Radiology; Radiotherapy; Radiotherapy Dosage; Radiotherapy in preclinical animal models; Resonance; Small animal radiation therapy; Tumor cell lines; Tumor cells; Tumors; X-Rays; Canada; Small animal radiation therapy; γ-H2AX; Magnetic resonance imaging; Breast cancer; Brain metastases; DNA double-strand breaks; Radiation dose-response
• ISSN: 1748-717X; 1748-717X
• DOI: 10.1186/s13014-018-1028-8

Background Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases’ responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations. Methods Half brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX immunohistochemistry at 30 min (acute) and 11 days (longitudinal) after half-brain treatment for doses of 8, 16 and 24 Gy. In addition, tumor responses were assessed volumetrically with in-vivo longitudinal MRI and histologically for tumor cell density and nuclear size. Results In the acute setting, γ-H2AX staining in tumors saturated at higher doses while normal mouse brain tissue continued to increase linearly in the phosphorylation of H2AX. While γ-H2AX fluorescence intensities returned to the background level in the brain 11 days after treatment, the residual γ-H2AX phosphorylation in the radiated tumors remained elevated compared to un-irradiated contralateral tumors. With radiation, MRI-derived relative tumor growth was significantly reduced compared to the un-irradiated side. While there was no difference in MRI tumor volume growth between 16 and 24 Gy, there was a significant reduction in tumor cell density from histology with increasing dose. In the longitudinal study, nuclear size in the residual tumor cells increased significantly as the radiation dose was increased. Conclusions Radiation damages to the DNAs in the normal brain parenchyma are resolved over time, but remain unrepaired in the treated tumors. Furthermore, there is a radiation dose response in nuclear size of surviving tumor cells. Increase in nuclear size together with unrepaired DNA damage indicated that the surviving tumor cells post radiation had continued to progress in the cell cycle with DNA replication, but failed cytokinesis. Half brain irradiation provides efficient evaluation of dose-response for cancer cell lines, a pre-requisite to perform experiments to understand radio-resistance in brain metastases.