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.
Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Sci Transl Med. 2015 Apr 1;7(281):281ra44. doi: 10.1126/scitranslmed.3010567.
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.
EphB 受体调节肠道干细胞和祖细胞的增殖和定位。此外，它们可以作为腺瘤发展的肿瘤促进剂，但抑制进展为浸润性癌。我们使用伊马替尼来废除 Apc(Min/+)小鼠和 LGR5(+)干细胞中的 Abl 激酶活性，这些干细胞经过基因工程改造后会发展出结肠腺瘤性息肉病。伊马替尼治疗抑制 EphB 信号的促肿瘤作用，而不减弱 EphB 介导的肿瘤抑制作用，表明 EphB 信号在肠道肿瘤的起始中起作用。伊马替尼治疗方案延长了 Apc(Min/+)小鼠的寿命，并减少了家族性腺瘤性息肉病患者腺瘤培养切片中的细胞增殖。这些发现将 EphB 信号通路与通过 Abl 激酶调节肠道腺瘤起始联系起来。我们的发现可能对易患结直肠癌的患者的腺瘤形成和癌症进展的药物治疗具有临床意义。
