Research ArticleCancer

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

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ra44
DOI: 10.1126/scitranslmed.3010567

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Imatinib holds adenomas in check

EphB receptors are known to regulate the proliferation and positioning of intestinal stem and progenitor cells. Although they act as tumor promoters for adenoma development, EphB receptors suppress progression to invasive carcinoma. Using a mouse model of familial adenomatous polyposis (FAP), Kundu et al. present evidence that the Abl kinase inhibitor imatinib specifically abrogates the tumor-promoting effect of EphB receptors without affecting EphB’s tumor suppressor functions. As a result, the life span of these mice is prolonged. Imatinib also reduced cell proliferation in cultured slices of adenomas from FAP patients, suggesting that this treatment might be a possibility for patients with FAP who are predisposed to develop colon cancer.

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 ApcMin/+ 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 ApcMin/+ 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.

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