An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth
| Autor: | Klas Strååt, Anna Martling, Maria Genander, Owen J. Sansom, Sven Pettersson, Rachel A. Ridgway, Parag Kundu, Jan Björk, Hans Clevers, Jonas Frisén, Ee Hong Tan, Johanna Classon, Johan H. van Es |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2015 |
| Předmět: |
Adenoma
Genes APC Adenomatous polyposis coli Carcinogenesis Longevity Ephrin-B2 medicine.disease_cause Research Support Familial adenomatous polyposis Mice Intestinal Neoplasms medicine Journal Article Animals Kinase activity Non-U.S. Gov't Proto-Oncogene Proteins c-abl Cell Proliferation ABL biology Research Support Non-U.S. Gov't Tumor Suppressor Proteins LGR5 General Medicine medicine.disease APC Imatinib mesylate Genes Immunology biology.protein Cancer research Imatinib Mesylate Stem cell Signal Transduction |
| Zdroj: | Science Translational Medicine, 7(281). American Association for the Advancement of Science (AAAS) Science Translational Medicine, 7(281), 281ra44. American Association for the Advancement of Science |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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