title: Endoscopy-guided orthotopic implantation of colorectal cancer cells results in metastatic colorectal cancer in mice.
abstract: Advanced stage colorectal cancer (CRC) is still associated with limited prognosis. For preclinical evaluation of novel therapeutic approaches, murine models with orthotopic tumor growth and distant metastases are required. However, these models usually require surgical procedures possibly influencing tumor immunogenicity and development. The aim of this study was to establish a minimal-invasive endoscopy-based murine orthotopic model of metastatic CRC. During colonoscopy of CD-1 nude and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, implantation of Caco-2 and HT-29 CRC cells was performed subcutaneously (s.c.) or orthotopic into the colonic submucosa. White light endoscopy (WLE) and fluorescence endoscopy (FE) were applied for tumor detection in vivo. Ex vivo, resected tumors were examined by fluorescence reflectance imaging (FRI), histology, gelatin zymography and immunohistochemistry. In CD-1 nude mice, marked tumor growth was observed within 14 days after subcutaneous implantation while submucosal implantation failed to induce CRC after 17 weeks. In contrast, in NOD/SCID mice submucosal injection of HT-29 cells resulted in pronounced tumor growth 12 days post injectionem. Subsequently, rapid tumor expansion occurred, occupying the entire colonic circumference. Importantly, post mortem histological analyses confirmed liver metastases in 28.6 % and peritoneal metastases in 14.3 % of all mice. FRI and gelatin zymography did not detect a significantly increased matrix metalloproteinases (MMPs) expression in s.c. implanted tumors while MMP-tracer uptake was significantly enhanced in orthotopic implanted tumors. Neither s.c. nor orthotopic Caco-2 cell implantation resulted in tumor development. We successfully established an endoscopy-based model of metastatic CRC in immunodeficient mice.
authors.affiliation: Department of Medicine B, University Hospital of Münster, Münster, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Bettenworth
authors.affiliation: Department of Medicine B, University Hospital of Münster, Münster, Germany.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Mücke
authors.affiliation: European Institute for Molecular Imaging, University of Münster, Münster, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schwegmann
authors.affiliation: European Institute for Molecular Imaging, University of Münster, Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.affiliation: Institute of Pathology Munich-North, Munich, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.affiliation: European Institute for Molecular Imaging, University of Münster, Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: Department of Medicine B, University Hospital of Münster, Münster, Germany.|Josephs-Hospital Warendorf, Warendorf, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Domagk
authors.affiliation: European Institute for Molecular Imaging, University of Münster, Münster, Germany. lenzph@uni-muenster.de.|Institute of Palliative Care, University Hospital of Münster, Albert-Schweitzer-Campus 1, Building W30, 48149, Münster, Germany. lenzph@uni-muenster.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Lenz
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology* / Q000601:surgery; D004195:Disease Models, Animal; D004724:Endoscopy / Q000379:methods*; D019073:HT29 Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000556:secondary* / Q000601:surgery; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D025321:Surgery, Computer-Assisted / Q000379:methods*
keywords: Colorectal cancer; Endoscopy; Fluorescence endoscopy; Fluorescence reflectance imaging; Matrix metalloproteinase; Metastasis