title: Ultrasound molecular imaging in a human CD276 expression-modulated murine ovarian cancer model.
abstract: OBJECTIVE
  To develop a mouse ovarian cancer model that allows modulating the expression levels of human vascular targets in mouse xenograft tumors and to test whether expression of CD276 during tumor angiogenesis can be visualized by molecularly targeted ultrasound in vivo.
  
  
  METHODS
  CD276-expressing MILE SVEN 1 (MS1) mouse endothelial cells were engineered and used for coinjection with 2008 human ovarian cancer cells for subcutaneous xenograft tumor induction in 15 nude mice. Fourteen control mice were injected with 2008 cells only. After confirming their binding specificity in flow chamber cell attachment studies, anti-CD276 antibody-functionalized contrast microbubbles were used for in vivo CD276-targeted contrast-enhanced ultrasound imaging.
  
  
  RESULTS
  CD276-targeted ultrasound imaging signal was significantly higher (P = 0.006) in mixed MS1/2008 tumors than in control tumors. Compared with control microbubbles, the ultrasound signal using CD276-targeted microbubbles was significantly higher (P = 0.002), and blocking with purified anti-CD276 antibody significantly decreased (P = 0.0096) the signal in mixed MS1/2008 tumors. Immunofluorescence analysis of the tumor tissue confirmed higher quantitative immunofluorescence signal in mixed MS1/2008 tumors than in control 2008 only tumors, but showed not significantly different (P = 0.54) microvessel density.
  
  
  CONCLUSIONS
  Our novel small animal model allows for modulating the expression of human tumor-associated vascular endothelial imaging targets in a mouse host and these expression differences can be visualized noninvasively by ultrasound molecular imaging. The animal model can be applied to other human vascular targets and may facilitate the preclinical development of new imaging probes such as microbubbles targeted at human vascular markers not expressed in mice.
authors.affiliation: Authors' Affiliations: Departments of Radiology and Bioengineering and Materials Science and Engineering; Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and Division of Public Health Sciences, Fred Hutchinson, Cancer Research Center, Seattle, Washington.
authors.forename: Amelie M
authors.initials: AM
authors.lastname: Lutz
authors.forename: Sunitha V
authors.initials: SV
authors.lastname: Bachawal
authors.forename: Charles W
authors.initials: CW
authors.lastname: Drescher
authors.forename: Marybeth A
authors.initials: MA
authors.lastname: Pysz
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Willmann
authors.forename: Sanjiv Sam
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003287:Contrast Media; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D051379:Mice; D045423:Microbubbles; D008856:Microscopy, Fluorescence; D057054:Molecular Imaging / Q000379:methods*; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D014463:Ultrasonography
chemical_list: D060887:B7 Antigens; C423237:CD276 protein, human; D003287:Contrast Media