title: Phase contrast MRI is an early marker of micrometastatic breast cancer development in the rat brain.
abstract: The early growth of micrometastatic breast cancer in the brain often occurs through vessel co-option 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 whether 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 10(6) MDA-MB-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 demonstrated that images of the signal phase (area under the receiver operating characteristic curve, 0.97) were more sensitive than T(2)* gradient echo magnitude images (area under the receiver operating characteristic curve, 0.73) to metastatic brain lesions. The difference between the two techniques was probably the result of the confounding effects of edema on the magnitude of the signal. A region of interest analysis revealed that vascular abnormalities detected with phase contrast MRI preceded tumor permeability measured with contrast-enhanced MRI by 1-2  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). Histopathologic analysis demonstrated that capillary endothelial cells co-opted by tumor cells were significantly enlarged, but less dense, relative to the normal brain vasculature. Although co-opted vessels were vascular endothelial growth factor-negative, vessels within larger tumor masses were vascular endothelial growth factor-positive. 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 preclinical studies of angiogenic-independent tumors or in the monitoring of continued tumor growth following anti-angiogenic therapy. Published 2011. This article is a US Government work and is in the public domain in the USA.
authors.affiliation: Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA. buddem@mail.nih.gov
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Budde
authors.forename: Eric
authors.initials: E
authors.lastname: Gold
authors.forename: E Kay
authors.initials: EK
authors.lastname: Jordan
authors.forename: Melissa
authors.initials: M
authors.lastname: Smith-Brown
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frank
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000097:blood / Q000098:blood supply / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000097:blood / Q000098:blood supply / Q000473:pathology*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry; D061206:Neoplasm Micrometastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous
chemical_list: D003287:Contrast Media; D003911:Dextrans; D006454:Hemoglobins; D058185:Magnetite Nanoparticles; C100003:deoxyhemoglobin; C065507:ferumoxides