Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance.
Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance.
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DOI：
10.1111/cas.13388
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发表时间：
2017-11
期刊：
影响因子：
5.7
通讯作者：
Hida Y
中科院分区：
文献类型：
--
作者：
Hida K;Maishi N;Akiyama K;Ohmura-Kakutani H;Torii C;Ohga N;Osawa T;Kikuchi H;Morimoto H;Morimoto M;Shindoh M;Shinohara N;Hida Y
肿瘤血管在肿瘤的进展和转移中起着重要的作用。我们以前报道过，与正常内皮细胞（NEC）相比，肿瘤内皮细胞（TEC）表现出几种改变的表型。例如，TEC有染色体异常，对几种抗癌药物有耐药性。此外，TEC含有具有高醛脱氢酶（ALDH）活性（ALDH高TEC）的干细胞样群体。与ALDH低TEC相比，ALDH高TEC具有促进血管生成的特性。然而，ALDH高TEC与耐药之间的关系尚不清楚。在本研究中，我们发现人和小鼠TEC中ALDH mRNA的表达和活性都高于NEC。人NEC：用肿瘤条件培养基（tumor CM）处理人微血管内皮细胞（HMVEC）。随着茎相关基因如多药耐药1、CD90、ALP和Oct - 4的上调，ALDH高人群增加。肿瘤CM也诱导了HMVEC的球形形成能力。肿瘤CM中的血小板衍生生长因子（PDGF）‐A可诱导HMVEC中ALDH的表达。ALDH高TEC体外和体内对氟尿嘧啶（5‐FU）均有耐药性。ALDH高TEC组的非整倍体程度高于ALDH低TEC组。这些结果表明，肿瘤分泌因子增加了ALDH高TEC人群对5‐FU的抗性。因此，肿瘤血管中ALDH高TEC可能是克服或预防耐药的重要靶点。
Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell‐like populations with high aldehyde dehydrogenase (ALDH) activity (ALDH high TEC). ALDH high TEC have proangiogenic properties compared with ALDH low TEC. However, the association between ALDH high TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC. Human NEC:human microvascular endothelial cells (HMVEC) were treated with tumor‐conditioned medium (tumor CM). The ALDH high population increased along with upregulation of stem‐related genes such as multidrug resistance 1, CD90, ALP, and Oct‐4. Tumor CM also induced sphere‐forming ability in HMVEC. Platelet‐derived growth factor (PDGF)‐A in tumor CM was shown to induce ALDH expression in HMVEC. Finally, ALDH high TEC were resistant to fluorouracil (5‐FU) in vitro and in vivo. ALDH high TEC showed a higher grade of aneuploidy compared with that in ALDH low TEC. These results suggested that tumor‐secreting factor increases ALDH high TEC populations that are resistant to 5‐FU. Therefore, ALDH high TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance.
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影响因子：
3.7
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
通讯作者：
Hida K
影响因子：
8.8
作者：
Osawa, T.;Ohga, N.;Akiyama, K.;Hida, Y.;Kitayama, K.;Kawamoto, T.;Yamamoto, K.;Maishi, N.;Kondoh, M.;Onodera, Y.;Fujie, M.;Shinohara, N.;Nonomura, K.;Shindoh, M.;Hida, K.
通讯作者：
Hida, K.
影响因子：
3.7
作者：
Kondoh M;Ohga N;Akiyama K;Hida Y;Maishi N;Towfik AM;Inoue N;Shindoh M;Hida K
通讯作者：
Hida K
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
3
作者：
Krzyzanowska, Monika K.;Tannock, Ian F.;Bjarnason, Georg A.
通讯作者：
Bjarnason, Georg A.