Ryschich Eduard, Lizdenis Paulius, Ittrich Carina, Benner Axel, Stahl Simone, Hamann Alf, Schmidt Jan, Knolle Percy, Arnold Bernd, Hämmerling Günter J, Ganss Ruth
Department of Surgery, University of Heidelberg, Germany.
Cancer Res. 2006 Jan 1;66(1):198-211. doi: 10.1158/0008-5472.CAN-05-1636.
In a mouse model of hepatocellular carcinogenesis, highly vascularized tumors develop through two distinct morphologic phases of neovascularization. We show that increased vascular caliber occurs first, followed by extensive vessel sprouting in late-stage carcinomas. To define molecular pathways in tumor neovascularization, endothelial cells were directly purified from normal liver and advanced tumors. Gene expression profiling experiments were then designed to identify genes enriched in the vascular compartment. We report that Cathepsin S is the major protease specifically overexpressed during vessel sprouting. We also show that the CC chemokines CCL2 and CCL3 are secreted by neovessels and stimulate proliferation through their cognate receptors in an autocrine fashion. This suggests that chemokine signaling represents the most prominent signaling pathway in tumor-associated endothelial cells and directly regulates vessel remodeling. Furthermore, high angiogenic activity is associated with attenuated lymphocyte extravasation and correlates with expression of the immunomodulatory cytokine interleukin 10. This is the first comprehensive study addressing liver-specific vascular changes in a murine autochthonous tumor model. These novel insights into liver angiogenesis infer an environmental control of neovascularization and have important implications for the design of antiangiogenic therapies.
在肝细胞癌发生的小鼠模型中，高度血管化的肿瘤通过两个不同的新生血管形成形态学阶段发展。我们发现血管口径首先增大，随后在晚期癌中出现广泛的血管芽生。为了确定肿瘤新生血管形成中的分子途径，从正常肝脏和晚期肿瘤中直接纯化内皮细胞。然后设计基因表达谱实验以鉴定在血管区室中富集的基因。我们报告组织蛋白酶S是在血管芽生期间特异性过度表达的主要蛋白酶。我们还表明，CC趋化因子CCL2和CCL3由新生血管分泌，并通过其同源受体以自分泌方式刺激增殖。这表明趋化因子信号传导是肿瘤相关内皮细胞中最突出的信号传导途径，并直接调节血管重塑。此外，高血管生成活性与淋巴细胞渗出减弱相关，并与免疫调节细胞因子白细胞介素10的表达相关。这是第一项针对小鼠原位肿瘤模型中肝脏特异性血管变化的综合研究。这些关于肝脏血管生成的新见解推断了对新生血管形成的环境控制，并对抗血管生成疗法的设计具有重要意义。
