title: An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth.
abstract: EphB receptors regulate the proliferation and positioning of intestinal stem and progenitor cells. In addition, they can act as tumor promoters for adenoma development but suppress progression to invasive carcinoma. We used imatinib to abrogate Abl kinase activity in Apc(Min/+) mice and in mice with LGR5(+) stem cells that were genetically engineered to develop adenomatous polyposis coli. Imatinib treatment inhibited the tumor-promoting effects of EphB signaling without attenuating EphB-mediated tumor suppression, demonstrating a role for EphB signaling in the initiation of intestinal tumors. The imatinib treatment regimen extended the life span of Apc(Min/+) mice and reduced cell proliferation in cultured slices of adenomas from patients with familial adenomatous polyposis. These findings connect the EphB signaling pathway to the regulation of intestinal adenoma initiation via Abl kinase. Our findings may have clinical implications for pharmacological therapy against adenoma formation and cancer progression in patients predisposed to develop colorectal cancer.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Parag
authors.initials: P
authors.lastname: Kundu
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Genander
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Strååt
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Classon
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Ee Hong
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Center for Digestive Diseases, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Björk
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Martling
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van Es
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637551, Singapore. The National Cancer Centre, Singapore General Hospital, Singapore 169610, Singapore. jonas.frisen@ki.se sven.pettersson@ki.se.
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. jonas.frisen@ki.se sven.pettersson@ki.se.
authors.forename: Jonas
authors.initials: J
authors.lastname: Frisén
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D036388:Ephrin-B2 / Q000378:metabolism*; D017491:Genes, APC; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008136:Longevity; D051379:Mice; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D036388:Ephrin-B2; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl