title: Characterization of an Orthotopic Colorectal Cancer Mouse Model and Its Feasibility for Accurate Quantification in Positron Emission Tomography.
abstract: OBJECTIVE
  Quantification in positron emission tomography (PET) imaging of an orthotopic mouse model of colorectal cancer (CRC) is challenging due to difficult tumor delineation. We aimed to establish a reproducible delineation approach, evaluate its feasibility for reliable PET quantification and compare its added translational value with its subcutaneous counterpart.
  
  
  METHODS
  A subcutaneous Colo205-luc2 tumor fragment harvested from a donor mouse was transplanted onto the caecum of nude mice, with (n = 10) or without (n = 10) the addition of an X-ray detectable thread. Animals underwent 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET imaging, complemented with X-ray computed tomography (CT) and magnetic resonance imaging (MRI, 7T). Animals without a thread underwent additional contrast enhanced (Exitron) CT imaging. Tumors were delineated on the MRI, μPET image or contrast enhanced μCT images and correlations between in vivo and ex vivo [18F]FDG tumor uptake as well as between image-derived and caliper-measured tumor volume were evaluated. Finally, cancer hallmarks were assessed immunohistochemically for the characterization of both models.
  
  
  RESULTS
  Our results showed the strongest correlation between both in vivo and ex vivo uptake (r = 0.84, p < 0.0001) and image-derived and caliper-measured tumor volume (r = 0.96, p < 0.0001) when the tumor was delineated on the MR image. Orthotopic tumors displayed an abundance of stroma, higher levels of proliferation (p = 0.0007), apoptosis (p = 0.02), and necrosis (p < 0.0001), a higher number of blood vessels (p < 0.0001); yet lower tumor hypoxia (p < 0.0001) as compared with subcutaneous tumors.
  
  
  CONCLUSIONS
  This orthotopic mouse model proved to be a promising tool for the investigation of CRC through preclinical imaging studies provided the availability of anatomical MR images for accurate tumor delineation. Furthermore, the tumor microenvironment of the orthotopic tumor resembled more that of human CRC, increasing its likelihood to advance translational nuclear imaging studies of CRC.
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Rapic
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
authors.forename: Christel
authors.initials: C
authors.lastname: Vangestel
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Verhaeghe
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van den Wyngaert
authors.affiliation: Bio-Imaging Lab (BIL), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Rukun
authors.initials: R
authors.lastname: Hinz
authors.affiliation: Bio-Imaging Lab (BIL), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Verhoye
authors.affiliation: Department of Pathological Anatomy, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.|Center for Oncological Research (CORE), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Sigrid.Stroobants@uza.be.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. Sigrid.Stroobants@uza.be.
authors.forename: Sigrid
authors.identifier: http://orcid.org/0000-0002-1285-9117
authors.initials: S
authors.lastname: Stroobants
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology*; D004195:Disease Models, Animal; D005240:Feasibility Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D040521:Subcutaneous Tissue / Q000473:pathology; D047368:Tumor Burden
keywords: Colorectal cancer; Contrast enhanced computed tomography; Magnetic resonance imaging; Orthotopic mouse model; Positron emission tomography; Tumor delineation