Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
PLoS One. 2014 Jan 15;9(1):e85759. doi: 10.1371/journal.pone.0085759. eCollection 2014.
The zebrafish (Danio rerio) and their transparent embryos represent a promising model system in cancer research. Compared with other vertebrate model systems, we had previously shown that the zebrafish model provides many advantages over mouse or chicken models to study tumor invasion, angiogenesis, and tumorigenesis. In this study, we systematically investigated the biological features of glioma stem cells (GSCs) in a zebrafish model, such as tumor angiogenesis, invasion, and proliferation. We demonstrated that several verified anti-angiogenic agents inhibited angiogenesis that was induced by xenografted-GSCs. We next evaluated the effects of a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy"), which revealed anti-tumor activity against human GSCs in vitro by establishing parameters through studying its ability to suppress angiogenesis, tumor invasion, and proliferation. Furthermore, our results indicated that Nordy might inhibit GSCs invasion and proliferation through regulation of the arachidonate 5-lipoxygenase (Alox-5) pathway. Moreover, the combination of Nordy and a VEGF inhibitor exhibited an enhanced ability to suppress angiogenesis that was induced by GSCs. By contrast, even following treatment with 50 µM Nordy, there was no discernible effect on zebrafish embryonic development. Together, these results suggested efficacy and safety of using Nordy in vivo, and further demonstrated that this model should be suitable for studying GSCs and anti-GSC drug evaluation.
斑马鱼（Danio rerio）及其透明胚胎是癌症研究中很有前途的模型系统。与其他脊椎动物模型系统相比，我们之前已经表明，斑马鱼模型在研究肿瘤侵袭、血管生成和肿瘤发生方面比小鼠或鸡模型具有许多优势。在这项研究中，我们系统地研究了斑马鱼模型中神经胶质瘤干细胞（GSCs）的生物学特征，如肿瘤血管生成、侵袭和增殖。我们证明了几种已验证的抗血管生成剂抑制了异种移植 GSCs 诱导的血管生成。接下来，我们评估了合成 dl-nordihydroguaiaretic 酸化合物（dl-NDGA 或“Nordy”）的效果，该化合物通过研究其抑制血管生成、肿瘤侵袭和增殖的能力来建立参数，在体外对人 GSCs 表现出抗肿瘤活性。此外，我们的结果表明，Nordy 可能通过调节花生四烯酸 5-脂氧合酶（Alox-5）途径来抑制 GSCs 的侵袭和增殖。此外，Nordy 与 VEGF 抑制剂的联合使用能够增强抑制 GSCs 诱导的血管生成的能力。相比之下，即使使用 50µM 的 Nordy 处理，也不会对斑马鱼胚胎发育产生明显影响。总之，这些结果表明 Nordy 在体内的有效性和安全性，进一步证明该模型应适用于研究 GSCs 和抗 GSC 药物评价。
