Abstract
Breast cancer is a major cause of morbidity and mortality in Western women. Tumor neoangiogenesis, the formation of new blood vessels from pre-existing ones, may be used as a prognostic marker for cancer progression. Clinical practice uses dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to detect cancers based on increased blood flow and capillary permeability. However, DCE-MRI requires repeated injections of contrast media. Therefore we explored the use of noninvasive time-of-flight (TOF) MR angiography for serial studies of mouse mammary glands to measure the number and size of arteries feeding mammary glands with and without cancer. Virgin female C3(1) SV40 TAg mice (n=9), aged 18-20 weeks, were imaged on a 9.4 Tesla small animal scanner. Multislice T2-weighted (T2W) images and TOF-MRI angiograms were acquired over inguinal mouse mammary glands. The data were analyzed to determine tumor burden in each mammary gland and the volume of arteries feeding each mammary gland. After in vivo MRI, inguinal mammary glands were excised and fixed in formalin for histology. TOF angiography detected arteries with a diameter as small as 0.1 mm feeding the mammary glands. A significant correlation (r=0.79; p< 0.0001) was found between tumor volume and the arterial blood volume measured in mammary glands. Mammary arterial blood volumes ranging from 0.08 mm3 to 3.81 mm3 were measured. Tumors and blood vessels found on in vivo T2W and TOF images, respectively, were confirmed with ex vivo histological images. These results demonstrate increased recruitment of arteries to mammary glands with cancer, likely associated with neoangiogenesis. Neoangiogenesis may be detected by TOF angiography without injection of contrast agents. This would be very useful in mouse models where repeat placement of I.V. lines is challenging. In addition, analogous methods could be tested in humans to evaluate the vasculature of suspicious lesions without using contrast agents.
Highlights
Breast cancer in humans is associated with increased blood supply and capillary permeability [1]
This study found a strong positive correlation between arterial blood volume in the mammary gland and mammary cancer volume using TOFA
The results demonstrate the effectiveness of TOFA for qualitative and quantitative measurements of changes in vasculature as cancer develops
Summary
Breast cancer in humans is associated with increased blood supply and capillary permeability [1]. Mammary vasculature is detected and evaluated using dynamic contrast enhanced (DCE) MRI [2]. This method requires rapid imaging following an I.V. injection of contrast media. Increased blood flow in cancers results in a greater rate of uptake of contrast media and more rapid enhancement in MR images. Changes in signal intensity following contrast media injection can be analyzed to determine contrast media uptake and to calculate physiological parameters relating to blood flow and permeability [2, 3]. While DCE-MRI is the preferred method for clinical detection of human breast cancer [4, 5], the use of DCEMRI for serial measurements in mouse models of breast cancer is challenging. DCEMRI requires rapid imaging with time resolution of 1–2 seconds; this means that signal-to-noise ratio and spatial resolution is limited [3]
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