Stemness marker ALDH1A1 promotes tumor angiogenesis via retinoic acid/HIF-1/VEGF signalling in MCF-7 breast cancer cells
Stemness marker ALDH1A1 promotes tumor angiogenesis via retinoic acid/HIF-1/VEGF signalling in MCF-7 breast cancer cells
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DOI：
10.1186/s13046-018-0975-0
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发表时间：
2018-12-12
影响因子：
11.3
通讯作者：
Ziche, Marina
中科院分区：
文献类型：
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作者：
Ciccone, Valerio;Terzuoli, Erika;Ziche, Marina
背景乙醛脱氢酶1A 1（ALDH 1A 1）是乙醛脱氢酶家族成员，是乳腺癌干细胞性的标志物。在肿瘤进展过程中，肿瘤干细胞（CSC）已被报道分泌血管生成因子，以协调病理性血管生成的形成。这种脉管系统可以代表CSC自我更新的来源和进一步肿瘤扩散的途径。本研究的目的是评估是否ALDH 1A 1控制乳腺癌细胞中的血管生成因子的输出，并调节肿瘤血管生成在体外和体内models.MethodsStemness状态的乳腺癌细胞的能力，以形成turmorspheres在体外进行了评估。使用transwell系统评估人脐静脉内皮细胞（HUVEC）与携带不同水平ALDH 1A 1的乳腺癌细胞MCF-7共培养时的血管生成特征。在这些条件下，我们研究了内皮细胞的增殖、迁移、管腔形成和渗透性。此外，在体内，MCF-7异种移植免疫缺陷小鼠允许评估血流量，血管生成因子和微血管密度（MVD）的表达。ResultsIn MCF-7，我们观察到，ALDH 1A 1活性赋予干属性和其表达与血管生成因子的激活。特别是，我们观察到缺氧诱导因子-1（HIF-1）和促血管生成因子（如血管内皮生长因子（VEGF））的显著上调。高水平的ALDH 1A 1通过维甲酸途径与VEGF介导的体外血管生成显著相关。HUVEC与表达ALDH 1A 1的肿瘤细胞共培养促进内皮细胞增殖、迁移、管形成和渗透性。相反，MCF-7中ALDH 1A 1的下调导致促血管生成因子的释放/表达减少和HUVEC血管生成功能受损。在体内，当皮下植入免疫缺陷小鼠，ALDH 1A 1过表达的乳腺肿瘤细胞表现出较高的VEGF和MVD的表达。ConclusionIn乳腺肿瘤，ALDH 1A 1表达引发一个允许的微环境，通过促进肿瘤血管生成通过视黄酸依赖的机制。因此，ALDH 1A 1可能与乳腺癌的进展和扩散有关。
BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models.MethodsStemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD).ResultsIn MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1 (HIF-1) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD.ConclusionIn breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.