Molecular targeted enhanced ultrasound imaging of flk1 reveals diagnosis and prognosis potential in a genetically engineered mouse prostate cancer model.
Molecular imaging techniques used to detect the initiation of disease have the potential to provide the best opportunity for early treatment and cure. This report aimed at testing the possibility that Flk1+ (vascular endothelial growth factor receptor 2), a crucial angiogenesis factor of most tumor cells, could be a molecular targeted imaging marker for the diagnosis and prognosis of cancer. We performed Flk1-targeted microbubble-enhanced ultrasound (US) imaging of prostate cancer in a genetically engineered mouse model with normal-appearing intact US (negative) prostates and with three different tumor sizes (small, medium, and large). Higher levels of Flk1+ molecular signals were identified in the intact US (negative) prostate group by US-targeted imaging and immunohistochemical analysis. The increase in Flk1+ expression occurred prior to the angiogenesis switch-on phase and vascularity peak. After this peak accumulation stage of Flk1+ molecules, lower and stabilized levels of Flk1+ signals were maintained together with tumor growth from small, to medium, to large size. In a longitudinal observation in a subset (n = 5) of mice with established tumors, elevated Flk1+ signals were observed in tissues surrounding the prostate cancer, for example, the ipsilateral boundary zones between two developing tumor lobes, new tumor blood vessel recruits, the urethra border, and the pelvic node basin. The potential of Flk1-targeted US imaging as a predictive imaging tool was confirmed by correlation studies of three-dimensional US B-mode imaging, gross pathology, and histology analyses. The results of the application in a genetically engineered mouse model with prostate cancer of molecular Flk1-targeted US imaging support the contention that Flk1 can be used as a molecular imaging marker for small tumors undetectable by microimaging and as a molecular diagnostic and prognosis marker for tumor metastasis and progression.
Xuan
Jim W
JW
Lawson Health Research Institute, Robarts Research Institute, London Regional Cancer Program, University of Western Ontario, London, ON. jim.xuan@lhsc.on.ca
Bygrave
Michael
M
Valiyeva
Fatma
F
Moussa
Madeleine
M
Izawa
Jonathan I
JI
Bauman
Glenn S
GS
Klibanov
Alexander
A
Wang
Fen
F
Greenberg
Norman M
NM
Fenster
Aaron
A
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage* / Q000032:analysis / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D055088:Early Detection of Cancer; D007091:Image Processing, Computer-Assisted / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000378:metabolism*
D014408:Biomarkers, Tumor; D003287:Contrast Media; D040301:Vascular Endothelial Growth Factor Receptor-2