旁分泌Hedgehog信号介导的肿瘤-间质能量转移在胰腺癌中的意义

项目名称： 旁分泌Hedgehog信号介导的肿瘤-间质能量转移在胰腺癌中的意义

项目编号： No.81472248

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马清涌

作者单位： 西安交通大学

项目金额： 75万元

中文摘要： 研究肿瘤微环境中不同细胞的生物学行为及肿瘤-间质细胞交互作用，对探索胰腺癌发病机制有重要意义。课题组在原承担的国家自然科学基金支持下，揭示了胰腺癌细胞旁分泌Sonic Hedgehog (SHH) 信号激活胰腺星状细胞后，促进胰腺癌神经浸润的分子机制。在研究过程中，我们发现被旁分泌SHH激活的星状细胞，能量代谢方式向有氧糖酵解方向转化。我们推测，胰腺癌细胞通过旁分泌SHH活化星状细胞，迫使其加快摄取葡萄糖并转向有氧糖酵解，释放高能量代谢产物乳酸反哺肿瘤细胞，并以此能量转移过程促进肿瘤生长和转移。为证实该假说，我们将从临床病理、体外细胞共培养、裸鼠胰腺癌模型三个层次，采用分子生物学、显微切割捕获、基因芯片、动物活体成像、磁共振波谱分析等技术，探究胰腺癌细胞旁分泌SHH对星状细胞能量代谢途径的影响，以及肿瘤-间质能量转移的分子机制，从新角度阐明星状细胞促进胰腺癌进展的机制。

中文关键词： C11_胰肿瘤；胰腺星状细胞；肿瘤-间质交互作用；糖代谢；Hedgehog通路

英文摘要： Increasing evidences indicate that exploration the various cell biology behavior and tumor-stroma interaction in tumor microenvironment may have great significance for the pancreatic cancer research. Under the support of National Natural Science Foundation, we have revealed the molecular mechanism involved in pancreatic cancer neural invasion, namely pancreatic cancer cell derived Sonic Hedgehog(SHH) induces activation of pancreatic stellate cells through classical Hedgehog(HH) signaling pathway. In addition, we found that this HH paracrine-mode activated stellate cells shift their energy metabolism to glycolysis form preferentially even under aerobic condition. Therefore, We speculate that there is an energy transfer process between pancreatic cancers and their surrounding stellate cells. HH paracrine-mode activated pancreatic stellate cells are forced to undergo aerobic glycolysis, and produce energy-rich nutrients (such as lactate) to feedcancer cells, result in tumor growth and metastasis. In order to verify this hypothesis, clinical pathology informations, co-culture mode in vitro and nude mouse model in vivo would be designed. To confirm this hypothesis, a variety of technology will be conducted, including molecular biology technology, Laser capture microscopic cutting, gene microarray, Optical in vivo Imaging technology, magnetic resonance spectrum analysis technology and so on. This important research will help us to reveal the molecular mechanisms involved in tumor-stroma energy transfer, giving new-insights to understand the promoting effects of pancreatic stellate cells on pancreatic cancer progression and providing potential therapeutic targets.

英文关键词： pancreatic cancer;pancreatic stellate cell;tumor-stroma interaction;glycometabolism;Hedgehog signaling