Noren Nicole K, Foos Gabriele, Hauser Craig A, Pasquale Elena B
Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Nat Cell Biol. 2006 Aug;8(8):815-25. doi: 10.1038/ncb1438. Epub 2006 Jul 23.
Recent evidence supports a role for EphB receptor tyrosine kinases as tumour suppressors in colorectal and prostate cancer. However, it is unclear how these receptors inhibit cancer cell tumorigenicity - an activity that is highly unusual for a family of receptor tyrosine kinases. Here, we report that the EphB4 receptor can behave as a tumour suppressor in a mouse xenograft model of breast cancer when stimulated by its ligand, ephrin-B2. In breast cancer cells, EphB4 activates an antioncogenic pathway involving Abl family tyrosine kinases and the Crk adaptor protein. This Abl-Crk pathway inhibits breast cancer cell viability and proliferation in addition to motility and invasion, and also downregulates the pro-invasive matrix metalloprotease, MMP-2. Consistent with these effects, EphB4 and the Abl-Crk pathway are constitutively active in non-transformed mammary epithelial cells. These findings identify a novel Eph receptor signalling pathway with tumour-suppressor activity and predict that therapeutic intervention to activate EphB4 signalling will inhibit tumour progression.
最近的证据支持EphB受体酪氨酸激酶在结直肠癌和前列腺癌中作为肿瘤抑制因子发挥作用。然而，尚不清楚这些受体如何抑制癌细胞的致瘤性——这一活性对于受体酪氨酸激酶家族来说非常罕见。在此，我们报告，当受到其配体ephrin-B2刺激时，EphB4受体在乳腺癌小鼠异种移植模型中可作为肿瘤抑制因子。在乳腺癌细胞中，EphB4激活一条涉及Abl家族酪氨酸激酶和Crk衔接蛋白的抗癌途径。这条Abl-Crk途径除了抑制乳腺癌细胞的活力、增殖、迁移和侵袭外，还下调促侵袭性基质金属蛋白酶MMP-2。与这些作用一致，EphB4和Abl-Crk途径在未转化的乳腺上皮细胞中组成性激活。这些发现确定了一条具有肿瘤抑制活性的新型Eph受体信号通路，并预测激活EphB4信号的治疗干预将抑制肿瘤进展。
