Functional neoangiogenesis imaging of genetically engineered mouse prostate cancer using three-dimensional power Doppler ultrasound.
We report the first application of high-frequency three-dimensional power Doppler ultrasound imaging 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.
Xuan
Jim W
JW
Department of Surgery, University of Western Ontario, London, Canada. jim.xuan@lhsc.ca
Bygrave
Michael
M
Jiang
Hongyi
H
Valiyeva
Fatma
F
Dunmore-Buyze
Joy
J
Holdsworth
David W
DW
Izawa
Jonathan I
JI
Bauman
Glenn
G
Moussa
Madeleine
M
Winter
Scott F
SF
Greenberg
Norman M
NM
Chin
Joseph L
JL
Drangova
Maria
M
Fenster
Aaron
A
Lacefield
James C
JC
D000230:Adenocarcinoma / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D004195:Disease Models, Animal; D005818:Genetic Engineering; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D018608:Ultrasonography, Doppler / Q000379:methods*