Abstract
Longitudinal MRI was applied to monitor intracranial initiation and development of brain metastases and assess tumor vascular volume and permeability in a mouse model of breast cancer brain metastases. Using a 9.4T system, high resolution anatomic MRI and dynamic susceptibility contrast (DSC) perfusion MRI were acquired at different time points after an intracardiac injection of brain-tropic breast cancer MDA-MB231BR-EGFP cells. Three weeks post injection, multifocal brain metastases were first observed with hyperintensity on T2-weighted images, but isointensity on T1-weighted post contrast images, indicating that blood-tumor-barrier (BTB) at early stage of brain metastases was impermeable. Follow-up MRI revealed intracranial tumor growth and increased number of metastases that distributed throughout the whole brain. At the last scan on week 5, T1-weighted post contrast images detected BTB disruption in 160 (34%) of a total of 464 brain metastases. Enhancement in some of the metastases was only seen in partial regions of the tumor, suggesting intratumoral heterogeneity of BTB disruption. DSC MRI measurements of relative cerebral blood volume (rCBV) showed that rCBV of brain metastases was significantly lower (mean = 0.89±0.03) than that of contralateral normal brain (mean = 1.00±0.03; p<0.005). Intriguingly, longitudinal measurements revealed that rCBV of individual metastases at early stage was similar to, but became significantly lower than that of contralateral normal brain with tumor growth (p<0.05). The rCBV data were concordant with histological analysis of microvascular density (MVD). Moreover, comprehensive analysis suggested no significant correlation among tumor size, rCBV and BTB permeability. In conclusion, longitudinal MRI provides non-invasive in vivo assessments of spatial and temporal development of brain metastases and their vascular volume and permeability. The characteristic rCBV of brain metastases may have a diagnostic value.
Highlights
Brain metastasis is the most common intracranial malignancy in adults
We have demonstrated the utility of longitudinal MRI to evaluate intracranial growth and vascularity of breast cancer brain metastases in a mouse model
Longitudinal monitoring of BTB permeability based on T1-weighted contrast enhanced images revealed that BTB in earlystage brain metastases were exclusively impermeable; even at the late stage, T1 contrast enhancement was only found in a small proportion (34%) of brain metastases, indicating that the BTB is still intact in the majority of the metastases (Figs. 2, 3 and 5)
Summary
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, with a median survival of 4–6 months even with aggressive treatment. Breast cancer is one of the three major primary cancers with a high morbidity of brain metastasis (15–25%) [1,2,3]. Advances in chemotherapy and immunotherapy played an important role in treating primary breast cancer as well as its systemic metastasis. The incidence of brain metastasis seems to have increased over the past decade, especially within patients undergoing these systematic therapies [5,6,7,8]. In part, this is due to the fact that most chemotherapeutic agents that show efficacy against systemic disease have poor penetration of bloodbrain barrier (BBB). Brain metastases containing an intact BBB are hereby inaccessible to the therapeutics and remain untreated [9,10,11]
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