肾癌细胞直接构筑肿瘤微血管的分子机制及临床意义

肾透明细胞癌血管极丰富且抗拒传统的放疗和化疗。血管生成抑制剂是目前仅存的有效治疗药物，但患者的生存获益有限。我们的初步研究显示肾癌中有部分CD31+ 的血管细胞来自肿瘤细胞；对其分子机制的初步探索更是发现HGF刺激可导致肾癌细胞转化成肾癌源血管细胞（RCOVC）、并构成血管样结构。通过运用三维细胞培养、原位肾癌动物模型、高通量基因芯片分析、回顾性研究，本项目将进一步探索营养缺乏及乏氧的微环境通过激活HGF/c-MET通路促进肾癌细胞形成RCOVC的分子机制；揭示调控RCOVC的关键信号通路；阐明RCOVC的形成过程是否可逆；评价RCOVC对血管生成抑制剂的抗药性；分析RCOVC的比重与病理分级、临床分期及生存预后的关系。本项目的完成将阐明肾癌细胞形成血管的分子机制及其临床意义，为将来研发出更有效的抗血管生成药物奠定理论基础。

Clear cell renal cell carcinoma (CCRCC) is a highly vascularized cancer resistant to conventional chemotherapy and radiotherapy. As a recent advance in the treatment of the patients with CCRCC, anti-angiogenic therapies have shown limited survival benefit. Our preliminary exploration found that some of the CD31+ cells forming blood vessels in CCRCC are actually cancer cells. Our further mechanistic study found that hepatocyte growth factor (HGF) stimulation could induce CCRCC cells to transform into renal cancer cell-originated blood-vessel cells (RCOVCs) and to form vascular structures in three-dimensional cell culture. In the present proposal, we will use three-dimensional cell culture systems, orthotopic renal tumor animal model, retrospective 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 RCOVCs both in vitro and in vivo. We will identify the key molecules and signaling pathway(s) in mediating RCOVC formation; determine whether RCOVC formation is a differentiation or a reversible cellular transformation process; and evaluate the susceptibility of RCOVC to angiogenesis inhibitors. We will also retrospectively analyze the relationship between the RCOVC ratio and CCRCC clinicopathological characteristics (including pathological grading, clinical staging, and patient survival). These findings will elucidate the molecular mechanisms of RCOVC formation, and aid in the development of more-specific and more-effective angiogenesis inhibitors for the CCRCC patients.