title: Detection of Early Murine Colorectal Cancer by MMP-2/-9-Guided Fluorescence Endoscopy.
abstract: BACKGROUND
  Patients with ulcerative colitis are at increased risk for colorectal cancer and endoscopic surveillance is mandatory. Matrix metalloproteinases (MMPs)-2 and -9 activities are increased in malignant colonic mucosa. The aim of the study was to evaluate molecular imaging of MMP-2/-9 by fluorescence endoscopy (FE) for early tumor detection.
  
  
  METHODS
  Colorectal cancer in mice (n = 28) was induced by azoxymethane and dextran sodium sulfate. Twenty-four hours after intravenous injection of a nonpeptidic, Cy5.5-labeled MMP-selective tracer, tumor development was assessed in vivo by white light endoscopy and FE. Topical administration of the tracer was also investigated (after 5 minutes and 24 hours). Colonic tumors were evaluated ex vivo by fluorescence reflectance imaging, immunohistochemistry, Western blot analysis, and zymography.
  
  
  RESULTS
  Imaging of MMP-2/-9 expression by FE achieved a significantly higher contrast of the fluorescence signal in colonic adenomas compared with the adjacent nonmalignant mucosa (P < 0.001). Fluorescence reflectance imaging detected a significantly higher tracer uptake in adenoma compared with healthy mucosa (P < 0.001) and revealed a tumor size-dependent increase of tracer uptake (P < 0.01). Topical tracer administration did not facilitate tumor detection. Immunohistochemistry, Western blot analysis, and zymography indicated higher levels of MMP-2 and -9 in high-grade dysplasia and pT1 tumors ex vivo.
  
  
  CONCLUSIONS
  MMP-2/-9 expression was significantly increased in colorectal neoplasia. FE allows direct visualization of a prognostic parameter (here MMP-2/-9) on a molecular level and may improve the characterization of colorectal lesions and the adenoma detection rate in the future.
authors.affiliation: *European Institute for Molecular Imaging, University of Münster, Münster, Germany; †Department of Medicine B, University Hospital Münster, Germany; ‡Institute of Pathology Munich-North, Munich, Germany; §Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Germany; and ‖Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Münster, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schwegmann
authors.forename: Dominik
authors.initials: D
authors.lastname: Bettenworth
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Dirk
authors.initials: D
authors.lastname: Domagk
authors.forename: Philipp
authors.initials: P
authors.lastname: Lenz
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002232:Carbocyanines / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000175:diagnosis* / Q000201:enzymology; D016264:Dextran Sulfate / Q000633:toxicity; D016099:Endoscopy, Gastrointestinal; D005260:Female; D007124:Immunoenzyme Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D061848:Optical Imaging / Q000379:methods*
chemical_list: C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D002273:Carcinogens; D016264:Dextran Sulfate; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D001397:Azoxymethane