Hyper-angiogenesis is a typical feature of glioblastoma (GBM), the most aggressive brain tumor. We have reported the expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in proliferating vasculature in GBM patients. We hypothesized that ALDH1A3 may act as an angiogenesis promoter in GBM. Two GBM cell lines were lentivirally transduced with either ALDH1A3 (ox) or an empty vector (ev). The angiogenesis phenotype was studied in indirect and direct co-culture of endothelial cells (ECs) with oxGBM cells (oxGBMs) and in an angiogenesis model in vivo. Angiogenesis array was performed in oxGBMs. RT2-PCR, Western blot, and double-immunofluorescence staining were performed to confirm the expression of targets identified from the array. A significantly activated angiogenesis phenotype was observed in ECs indirectly and directly co-cultured with oxGBMs and in vivo. Overexpression of ALDH1A3 (oxALDH1A3) led to a marked upregulation of PAI-1 and IL-8 mRNA and protein and a consequential increased release of both proteins. Moreover, oxALDH1A3-induced angiogenesis was abolished by the treatment of the specific inhibitors, respectively, of PAI-1 and IL-8 receptors, CXCR1/2. This study defined ALDH1A3 as a novel angiogenesis promoter. oxALDH1A3 in GBM cells stimulated EC angiogenesis via paracrine upregulation of PAI-1 and IL-8, suggesting ALDH1A3-PAI-1/IL-8 as a novel signaling for future anti-angiogenesis therapy in GBM.
过度血管生成是胶质母细胞瘤（GBM）——最具侵袭性的脑肿瘤——的典型特征。我们先前报道了醛脱氢酶1A3（ALDH1A3）在GBM患者增殖血管系统中的表达。我们假设ALDH1A3可能在GBM中发挥促血管生成作用。通过慢病毒转导技术，我们在两种GBM细胞系中分别过表达ALDH1A3（ox组）或转入空载体（ev组）。通过内皮细胞（ECs）与过表达ALDH1A3的GBM细胞（oxGBMs）的间接和直接共培养体系，以及体内血管生成模型，研究了血管生成表型。对oxGBMs进行了血管生成因子阵列分析，并采用RT2-PCR、Western印迹和双免疫荧光染色验证了阵列中筛选出的靶标表达。在与oxGBMs间接和直接共培养的内皮细胞以及体内模型中，均观察到显著激活的血管生成表型。ALDH1A3的过表达（oxALDH1A3）导致纤溶酶原激活物抑制剂-1（PAI-1）和白介素-8（IL-8）的mRNA和蛋白水平显著上调，并相应增加了这两种蛋白的释放。此外，分别使用PAI-1特异性抑制剂和IL-8受体CXCR1/2特异性抑制剂处理，可消除oxALDH1A3诱导的血管生成作用。本研究确立了ALDH1A3作为一种新型促血管生成因子。GBM细胞中oxALDH1A3通过旁分泌上调PAI-1和IL-8刺激内皮细胞血管生成，提示ALDH1A3-PAI-1/IL-8信号通路可作为未来GBM抗血管生成治疗的新靶点。
肿瘤(癌症)患者之家