Hida Kyoko, Maishi Nako, Akiyama Kosuke, Ohmura-Kakutani Hitomi, Torii Chisaho, Ohga Noritaka, Osawa Takahiro, Kikuchi Hiroshi, Morimoto Hirofumi, Morimoto Masahiro, Shindoh Masanobu, Shinohara Nobuo, Hida Yasuhiro
Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Cancer Sci. 2017 Nov;108(11):2195-2203. doi: 10.1111/cas.13388. Epub 2017 Sep 17.
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 TEC). ALDH TEC have proangiogenic properties compared with ALDH TEC. However, the association between ALDH 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 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 TEC were resistant to fluorouracil (5-FU) in vitro and in vivo. ALDH TEC showed a higher grade of aneuploidy compared with that in ALDH TEC. These results suggested that tumor-secreting factor increases ALDH TEC populations that are resistant to 5-FU. Therefore, ALDH TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance.
肿瘤血管在肿瘤进展和转移中起着重要作用。我们之前报道过，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存在染色体异常，并且对几种抗癌药物具有抗性。此外，TEC包含具有高醛脱氢酶（ALDH）活性的干细胞样群体（ALDH TEC）。与ALDH TEC相比，ALDH TEC具有促血管生成特性。然而，ALDH TEC与耐药性之间的关联仍不清楚。在本研究中，我们发现人源和小鼠源的TEC中ALDH mRNA表达和活性均高于NEC。用人肿瘤条件培养基（肿瘤CM）处理人NEC：人微血管内皮细胞（HMVEC）。随着多药耐药1、CD90、碱性磷酸酶和Oct-4等干细胞相关基因上调以及ALDH群体增加。肿瘤CM还诱导了HMVEC的成球能力。肿瘤CM中的血小板衍生生长因子（PDGF）-A被证明可诱导HMVEC中ALDH表达升高。最后，ALDH TEC在体外和体内对氟尿嘧啶（5-FU）均具有抗性。与ALDH TEC相比，ALDH TEC显示出更高程度的非整倍体现象。这些结果表明肿瘤分泌因子增加了对5-FU具有抗性的ALDH TEC群体。因此肿瘤血管中的ALDH TEC可能是克服或预防耐药性的一个重要靶点。
