Wnt5a调控鼻咽癌转移的细胞结构、受体分析和信号通路

鼻咽癌作为华南及东南亚地区的高发恶性肿瘤，其远处转移是治疗失败的主要原因。我们基于自创的鼻咽癌淋巴结转移模型，通过高通量的基因表达谱分析，首次发现Wnt5a 的表达水平与鼻咽癌细胞转移能力呈正相关。但是Wnt5a调控鼻咽癌转移的分子机制未明。我们的预实验显示，鼻咽癌淋巴结和肝转移灶中Wnt5a 表达水平比原发灶显著升高。我们因此提出了Wnt5a与细胞膜受体相结合之后调控鼻咽癌细胞的迁移、侵袭和转移能力的科学假设。通过应用裸小鼠淋巴结转移模型以及液相色谱与串联质谱等技术，本项目将进一步收集Wnt5a上调鼻咽癌转移的系列证据、鉴定Wnt5a在鼻咽癌细胞通过Cdc42调控丝状伪足的形成、识别Wnt5a在鼻咽癌细胞的膜受体、明确Wnt5a的信号通路以及该通路上的关键分子。本项目的完成将阐明Wnt5a调控鼻咽癌转移的分子机理、为预测患者的预后以及防治鼻咽癌的远处转移提供新的靶点。

Nasopharyngeal carcinoma (NPC) is a highly vascularized cancer resistant to conventional chemotherapy and radiotherapy. As a recent advance in the treatment of the patients with NPC, anti-angiogenic therapies have shown limited survival benefit. Our previous study revealed that the undifferentiated microvessel density in NPC is an independent unfavorable prognostic factor for patients. Further exploration found that some of the CD31+ cells forming blood vessels in CCRCC are actually cancer cells. An in vitro three-dimensional cell culture study showed that NPC cells could transform into renal cancer cell-originated blood-vessel cells (RCOBCs) and form vascular structures under the stimulation of hepatocyte growth factor (HGF). In the present proposal, we will use three-dimensional cell culture systems, orthotopic renal tumor animal model, retrospective as well as prospective clinical studies to fulfill 7 research aims. We will determine whether nutrient deprivation or hypoxia triggers the HGF/c-Met pathway for promoting the formation of RCOBCs both in vitro and in vivo. We will identify what endothelial markers are expressed in RCOBCs; determine whether RCOBC formation is a differentiation or a reversible cellular transformation process; and evaluate the susceptibility of RCOBC to angiogenesis inhibitors.