Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype.
Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype.
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DOI：
10.1371/journal.pone.0113910
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hida K
中科院分区：
文献类型：
--
作者：
Ohmura-Kakutani H;Akiyama K;Maishi N;Ohga N;Hida Y;Kawamoto T;Iida J;Shindoh M;Tsuchiya K;Shinohara N;Hida K
肿瘤血管在肿瘤的进展和转移中起着重要的作用。据报道，与正常内皮细胞（NECs）相比，肿瘤内皮细胞（tec）表现出高度的血管生成表型。与nec相比，TECs具有更高的增殖和迁移能力，且血管内皮生长因子（VEGF）和VEGF受体2 （VEGFR2）表达上调。此外，与nec相比，干细胞标志物如Sca-1、CD90和多药耐药1在tec中上调，表明肿瘤血管中存在干细胞样细胞。在本研究中，为了揭示干细胞样tec的生物学作用，我们分析了干细胞标志物醛脱氢酶（ALDH）在tec中的表达，并对ALDH高的tec进行了表征。分别从移植黑色素瘤的裸鼠和正常真皮中分离出tec和nec。ALDH mRNA在TECs中的表达和活性高于NECs。接下来，通过荧光活化细胞分选分离ALDHhigh/low TECs，比较它们的特性。与ALDHlow tec相比，ALDHhigh tec在matrigel涂层板上形成了更多的管，并且维持了更长时间的管状网络。此外，VEGFR2在ALDHhigh TECs中的表达高于ALDHlow TECs。此外，ALDH在黑色素瘤和口腔癌小鼠体内模型的肿瘤血管中表达，而在正常血管中不表达。这些发现表明ALDHhigh tec表现出血管生成表型。茎样tec可能在肿瘤血管生成中起重要作用。
Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis.