肿瘤的生长和转移是血管生成依赖的，因此抗血管生成治疗是目前临床肿瘤保守治疗的重要手段之一，但肿瘤的抗血管生成耐受严重影响了疗效。揭示抗血管生成耐受的机制将为开发新的抗血管生成药物提供重要实验依据。最近发现，肿瘤血管中存在肿瘤干细胞分化形成的内皮细胞可能是肿瘤抗血管生成耐受的主要原因。我们的前期研究表明，肝癌干细胞具有分化的可塑性，具有分化为多种细胞类型的潜能，且Oct4在这种多向分化潜能中起了关键性的作用。因此我们推测肝癌的抗血管生成耐受与肝癌干细胞向内皮细胞分化潜能有关，且该潜能受Oct4调控。本研究拟应用已建立的高表达及低表达Oct4的肝癌干细胞单细胞克隆作为研究对象，通过体外和体内实验，比较其向内皮细胞的分化潜能，以及对抗血管生成药物耐受情况，探索Oct4对肝癌干细胞向血管内皮细胞分化的调控作用及机制，为阐明肝癌抗血管生成耐受的机制和开发抗血管生成治疗新药提供实验依据。

Growth and metastasis of cancer are angiogenesis-dependent. Anti-angiogenesis treatment is an important therapy for cancers in clinic. But the tolerance of cancer to anti-angiogenic drugs has seriously discounted the efficacy. It will provided important experimental data to elucidate the mechanism of anti-angiogenic tolerance for developing new anti-angiogenic drugs and improving the efficacy. Recently, endothelial cells derived from cancer stem cells (CSCs) were found existing in cancer vascular walls, which might be one reason of tolerance of cancer to anti-angiogenic drugs. Our previous work showed that human liver CSCs had pluripotency: a single-cloned CSC had the potential of differentiating into different type of cells, and Oct4 was indispensable in this process. Therefore, we presumed that the potential of CSCs differentiating toward endothelial cells contributes to the tolerance of cancer to anti-angiogenesis treatment, and Oct4 is a key regulation factor. In this study, using the established single-cloned CSCs with Oct4high and Oct4low, we will first compare their potential of differentiating toward endothelial cells in vitro and in vivo; then investigate the tolerance of endothelial cells differentiated from CSCs to anti-angiogenic drugs in vitro and in vivo; furthermore, the mechanism of Oct4 contributing to this process will be studied and the effect of intervene Oct4 on anti-angiogenesis treatment will be analyzed as well. This study is important for unraveling the mechanism of cancer tolerance to anti-angiogenesis treatment and will provide important data for developing new anti-angiogenic drugs.