title: Functional Genomic mRNA Profiling of Colorectal Adenomas: Identification andin vivoValidation of CD44 and Splice Variant CD44v6 as Molecular Imaging Targets.
abstract: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. High adenoma miss rates, especially seen in high-risk patients, demand for better endoscopic detection. By fluorescently 'highlighting' specific molecular characteristics, endoscopic molecular imaging has great potential to fulfill this need. To implement this technique effectively, target proteins that distinguish adenomas from normal tissue must be identified. In this study we appliedin silicoFunctional Genomic mRNA (FGmRNA) profiling, which is a recently developed method that results in an enhanced view on the downstream effects of genomic alterations occurring in adenomas on gene expression levels. FGmRNA profiles of sporadic adenomas were compared to normal colon tissue to identify overexpressed genes. We validated the protein expression of the top identified genes,AXIN2, CEMIP, CD44andJUN, in sporadic adenoma patient samples via immunohistochemistry (IHC). CD44 was identified as the most attractive target protein for imaging purposes and we proved its relevance in high-risk patients by demonstrating CD44 protein overexpression in Lynch lesions. Subsequently, we show that the epithelial splice variant CD44V6 is highly overexpressed in our patient samples and we demonstrated the feasibility of visualizing adenomas inApcMin/+micein vivoby using a fluorescently labeled CD44v6 targeting peptide. In conclusion, viain silicofunctional genomics andex vivoprotein validation, this study identified CD44 as an attractive molecular target for both sporadic and high-risk Lynch adenomas, and demonstrates thein vivoapplicability of a small peptide drug directed against splice variant CD44v6 for adenoma imaging.
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Elmire
authors.initials: E
authors.lastname: Hartmans
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Veronique
authors.initials: V
authors.lastname: Orian-Rousseau
authors.affiliation: Amcure GmbH, Eggenstein-Leopolshafen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Matzke-Ogi
authors.affiliation: Department of Pathology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Arend
authors.initials: A
authors.lastname: Karrenbeld
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Derk Jan A
authors.initials: DJ
authors.lastname: de Groot
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: de Jong
authors.affiliation: Department of Surgery, Nuclear Medicine and Molecular Imaging and Intensive Care, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Gooitzen M
authors.initials: GM
authors.lastname: van Dam
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Wouter B
authors.initials: WB
authors.lastname: Nagengast
mesh_terms: D000236:Adenoma / Q000175:diagnosis* / Q000473:pathology; D000818:Animals; D003113:Colonoscopy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000473:pathology; D003955:Diagnostic Tests, Routine / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis* / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
chemical_list: C497483:CD44 protein, human; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; D012333:RNA, Messenger
keywords: CD44 / CD44v6.; Cancer Genetics; Colorectal adenomas; Functional Genomics; Molecular Targeted Imaging