Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Hokkaido, Japan.
Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Hokkaido, Japan; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
Am J Pathol. 2012 Mar;180(3):1294-1307. doi: 10.1016/j.ajpath.2011.11.035. Epub 2012 Jan 12.
An important concept in tumor angiogenesis is that tumor endothelial cells (TECs) are genetically normal and homogeneous. However, we previously reported that TECs differ from normal ECs. Whether the characteristics of TECs derived from different tumors differ remains unknown. To elucidate this, in this study, we isolated two types of TECs from high-metastatic (HM) and low-metastatic (LM) tumors and compared their characteristics. HM tumor-derived TECs (HM-TECs) showed higher proliferative activity and invasive activity than LM tumor-derived TECs (LM-TECs). Moreover, the mRNA expression levels of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF) receptors 1 and 2, VEGF, and hypoxia-inducible factor-1α, were higher in HM-TECs than in LM-TECs. The tumor blood vessels themselves and the surrounding area in HM tumors were exposed to hypoxia. Furthermore, HM-TECs showed higher mRNA expression levels of the stemness-related gene stem cell antigen and the mesenchymal marker CD90 compared with LM-TECs. HM-TECs were spheroid, with a smoother surface and higher circularity in the stem cell spheroid assay. HM-TECs differentiated into osteogenic cells, expressing activated alkaline phosphatase in an osteogenic medium at a higher rate than either LM-TECs or normal ECs. Furthermore, HM-TECs contained more aneuploid cells than LM-TECs. These results indicate that TECs from HM tumors have a more pro-angiogenic phenotype than those from LM tumors.
肿瘤血管生成中的一个重要概念是肿瘤内皮细胞（TEC）在遗传上是正常且同质的。然而，我们之前曾报道过 TEC 与正常 EC 不同。不同肿瘤来源的 TEC 是否具有不同的特征尚不清楚。为了阐明这一点，在本研究中，我们从高转移性（HM）和低转移性（LM）肿瘤中分离出两种类型的 TEC，并比较了它们的特征。HM 肿瘤来源的 TEC（HM-TEC）比 LM 肿瘤来源的 TEC（LM-TEC）具有更高的增殖活性和侵袭活性。此外，HM-TEC 中促血管生成基因如血管内皮生长因子（VEGF）受体 1 和 2、VEGF 和缺氧诱导因子-1α 的 mRNA 表达水平高于 LM-TEC。HM 肿瘤中的肿瘤血管本身及其周围区域处于缺氧状态。此外，HM-TEC 中与干细胞相关的基因干细胞抗原和间充质标记物 CD90 的 mRNA 表达水平高于 LM-TEC。与 LM-TEC 相比，HM-TEC 在干细胞球体测定中呈球体状，表面更光滑，圆形度更高。HM-TEC 在成骨培养基中以更高的速率分化为成骨细胞，表达激活的碱性磷酸酶。此外，HM-TEC 比 LM-TEC 含有更多的非整倍体细胞。这些结果表明，来自 HM 肿瘤的 TEC 比来自 LM 肿瘤的 TEC 具有更强的促血管生成表型。
