Noren Nicole K, Lu Mark, Freeman Andrew L, Koolpe Mitchell, Pasquale Elena B
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5583-8. doi: 10.1073/pnas.0401381101. Epub 2004 Apr 5.
Receptor tyrosine kinases of the Eph family are up-regulated in different types of cancer. EphB4 and its ligand ephrin-B2 have been linked to breast cancer, but little is known about how this receptor-ligand complex may contribute to oncogenesis. The Eph receptors transmit forward signals via their kinase domain and reverse signals via their transmembrane ephrin-B ligands. Therefore, we used EphB4 that were lacking the kinase domain and tagged with EGFP (EphB4 Delta C-EGFP) to differentiate between EphB4 and ephrin-B2 signaling. Interestingly, we found that expression of EphB4 Delta C-EGFP in breast cancer cells increases tumor growth in a mouse xenograft model. Given the undetectable EphB4 activation in the tumor cells, dominant negative effects of EphB4 Delta C-EGFP are unlikely to explain the increased tumor growth. Examination of the tumors revealed that ephrin-B2 is primarily expressed in the vasculature and that the EphB4 Delta C-EGFP tumors have a higher blood content than control tumors, concomitant with increased size of blood vessels. In support of an effect on the vasculature, the extracellular domain of EphB4 attracts endothelial cells in vitro and stimulates endothelial cell invasion, survival, and proliferation, all crucial factors for angiogenesis. These results support a model in which EphB4 promotes tumor growth by stimulating angiogenesis through ephrin-B2.
Eph家族的受体酪氨酸激酶在不同类型的癌症中上调。EphB4及其配体ephrin - B2与乳腺癌有关，但对于这种受体 - 配体复合物如何促进肿瘤发生知之甚少。Eph受体通过其激酶结构域传递正向信号，并通过其跨膜ephrin - B配体传递反向信号。因此，我们使用缺乏激酶结构域并标记有EGFP的EphB4（EphB4 Delta C - EGFP）来区分EphB4和ephrin - B2信号。有趣的是，我们发现在小鼠异种移植模型中，乳腺癌细胞中EphB4 Delta C - EGFP的表达增加了肿瘤生长。鉴于肿瘤细胞中未检测到EphB4激活，EphB4 Delta C - EGFP的显性负效应不太可能解释肿瘤生长的增加。对肿瘤的检查显示，ephrin - B2主要在脉管系统中表达，并且EphB4 Delta C - EGFP肿瘤的血液含量高于对照肿瘤，同时血管大小增加。为支持对脉管系统的影响，EphB4的细胞外结构域在体外吸引内皮细胞并刺激内皮细胞侵袭、存活和增殖，这些都是血管生成的关键因素。这些结果支持了一个模型，即EphB4通过ephrin - B2刺激血管生成来促进肿瘤生长。
