Format

Send to

Choose Destination
Sci Transl Med. 2015 Apr 1;7(281):281ra44. doi: 10.1126/scitranslmed.3010567.

An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth.

Author information

1
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.
2
Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
3
Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
4
Center for Digestive Diseases, Karolinska Institute, SE-171 77 Stockholm, Sweden.
5
Department of Molecular Medicine and Surgery, Karolinska Institute, SE-171 77 Stockholm, Sweden.
6
Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, Netherlands.
7
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.
8
Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. jonas.frisen@ki.se sven.pettersson@ki.se.

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.

PMID:
25834110
DOI:
10.1126/scitranslmed.3010567
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center