Functional Neoangiogenesis Imaging of Genetically Engineered Mouse Prostate Cancer Using Three-Dimensional Power Doppler Ultrasound.
Jim W. Xuan,1, Michael Bygrave6, Hongyi Jiang1, Fatma Valiyeva1, Joy Dunmore-Buyze6, David W. Holdsworth2,6, Jonathan I. Izawa1, Glenn Bauman3, Madeleine Moussa4, Scott F. Winter7, Norman M. Greenberg7, Joseph L. Chin1, Maria Drangova2,6, Aaron Fenster2,3,6 and James C. Lacefield2,5,6
Departments of 1 Surgery, 2 Medical Biophysics, 3 Oncology, 4 Pathology, and 5 Electrical and Computer Engineering, University of Western Ontario and 6 Imaging Research Laboratories, Robarts Research Institute, London, Ontario, Canada; and 7 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
Cancer Research 67, 2830-2839, March 15, 2007





Brief Summary:
  • > We report the first application of high-frequency three-dimensional power Doppler ultrasound imaging (Vevo 770, VisualSonics) in a genetically engineered mouse (GEM) prostate cancer model. We show that the technology sensitively and specifically depicts functional neoangiogenic blood flow because little or no flow is measurable in normal prostate tissue or tumors smaller than 2–3 mm diameter, the neoangiogenesis "switch-on" size. Vascular structures depicted by power Doppler were verified using Microfil-enhanced micro-computed tomography (micro-CT) and by correlation with microvessel distributions measured by immunohistochemistry and enhanced vascularity visualized by confocal microscopy in two GEM models [transgenic adenocarcinoma of the mouse prostate (TRAMP) and PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP)]. Four distinct phases of neoangiogenesis in cancer development were observed, specifically, (a) an early latent phase; (b) establishment of a peripheral capsular vascular structure as a neoangiogenesis initiation site; (c) a peak in tumor vascularity that occurs before aggressive tumor growth; and (d) rapid tumor growth accompanied by decreasing vascularity. Microsurgical interventions mimicking local delivery of antiangiogenesis drugs were done by ligating arteries upstream from feeder vessels branching to the prostate. Microsurgery produced an immediate reduction of tumor blood flow, and flow remained low from 1 h to 2 weeks or longer after treatment. Power Doppler, in conjunction with micro-CT, showed that the tumors recruit secondary blood supplies from nearby vessels, which likely accounts for the continued growth of the tumors after surgery. The microsurgical model represents an advanced angiogenic prostate cancer stage in GEM mice corresponding to clinically defined hormone-refractory prostate cancer. Three-dimensional power Doppler imaging is completely noninvasive and will facilitate basic and preclinical research on neoangiogenesis in live animal models. [Cancer Res 2007;67(6):2830–9]