An EphB-Abl signaling pathway important for intestinal tumor initiation and growth

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. Here we used imatinib to abrogate Abl kinase activity in ApcMin/+ mice and in mice with LGR5+ stem cells genetically targeted for APC. This treatment inhibited the tumor-promoting effects of EphB signaling without attenuating EphB-mediated tumor suppression, demonstrating the role of EphB signaling in intestinal tumor initiation. The investigated treatment regimen extended the lifespan of ApcMin/+ mice, and reduced cell proliferation in cultured slices of adenomas from FAP patients. 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 colon cancer. We used microarray to assess the short term (3h and 12h) effects on gene expression in colon stem and progenitor cells after administration of Imatinib. Colon samples were obtained at different timepoints after injection of Imatinib and processes for RNA extraction and hybridization for Affymetrix array.