Phase Contrast MRI is an Early Marker of Micrometastatic Breast Cancer Development in the Rat Brain

The early growth of micrometastatic breast cancer in the brain often occurs through vessel cooption and is independent of angiogenesis. Remodeling of the existing vasculature is an important step in the evolution of co-opting micrometastases into angiogenesis-dependent solid tumor masses. The purpose of this study was to determine if phase contrast MRI, an intrinsic source of contrast exquisitely sensitive to the magnetic susceptibility properties of deoxygenated hemoglobin, could detect vascular changes occurring independent of angiogenesis in a rat model of breast cancer metastases to the brain. Twelve nude rats were administered with 10 6 MDAMB-231BRL “brain seeking” breast cancer cells through intracardiac injection. Serial, multiparametric MRI of the brain was performed weekly until metastatic disease was detected. The results demonstrate that images of the signal phase were more sensitive to metastatic brain lesions (area under receiver operating characteristic curve, AUC = 0.97) compared to T2* gradient echo magnitude images, (AUC = 0.73). The difference between the two techniques was likely the result of the confounding effects of edema on the magnitude signal. A region of interest analysis revealed that vascular abnormalities detected with phase contrast MRI preceded tumor permeability as measured with contrast-enhanced MRI by 1 to 2 weeks. Tumor size was correlated with permeability (R 2 = 0.23, p < 0.01), but phase contrast was independent of tumor size (R 2 = 0.03). Histopathological analysis demonstrated that capillary endothelial cells coopted by tumor cells were significantly enlarged, but less dense, compared to the normal brain vasculature. Whereas co-opted vessels were VEGF-negative, vessels within larger tumor masses were VEGFpositive. In conclusion, phase contrast MRI is believed to be sensitive to vascular remodeling in co-opting brain tumor metastases independent of sprouting angiogenesis and may therefore aid in pre-clinical studies of angiogenic-independent tumors or monitoring continued tumor growth following anti-angiogenic therapy.