胰腺星状细胞Caveolin-1-ROS正反馈介导胰腺癌间质-肿瘤形成代谢共同体促进胰腺癌的进展

Tumor interstitial microenvironment plays a vital role in tumor initiation and progression. We recently showed that pancreatic stellate cells (PSCs) could be activated by self-generated ROS under hypoxia exposure, and activated PSCs could significantly enhance pancreatic cancer invasion. In our further study, we found that upregulation of ROS in PSCs could suppress its Caveolin-1 (Cav-1) expression, however, decrease in Cav-1 expression could in turn increase the ROS expression, leading to a Cav-1-ROS feedforward in PSCs. Intriguingly, we found that during the Cav-1-ROS feedforward, PSCs transformed their energy metabolism into a preferentially glycolysis even under aerobic conditions. Thus, we speculate that Cav-1-ROS feedforward in PSCs could shift PSC energy metabolism to glycolysis to generate lots of energy-rich nutrients (such as lactate) to fuel the pancreatic cancer cells, which leads to the metabolic coupling between PSCs and pancreatic cancer cells. To test our hypothesis, clinical pathology informations, co-culture mode in vitro and nude mouse model would be designed and lots of technologies such as molecular biology technology, Laser capture microscopic cutting, Optical in vivo Imaging technology will be conducted. This study will help us to delineate the molecular mechanisms of PSC Cav-1-ROS feedforward in promoting tumor-stroma to form the metabolic coupling, shining new-lights to understand the promoting effects of pancreatic stellate cells on pancreatic cancer progression and provide potential therapeutic targets.

肿瘤微环境中间质对肿瘤的发生发展起着关键作用。课题组最近研究发现胰腺星状细胞在缺氧条件下能够被自身产生的ROS活化，活化的星状细胞能够明显增强胰腺癌的侵袭能力；星状细胞中ROS水平上调能够下调Caveolin-1(Cav-1)表达，而Cav-1下调又能促进ROS上调，存在Cav-1-ROS正反馈，在这一正反馈过程中星状细胞能量代谢转向有氧糖酵解方式。我们推测星状细胞的Cav-1-ROS正反馈能够诱导星状细胞摄取葡萄糖进行有氧糖酵解，释放乳酸等代谢产物到周围间质为肿瘤细胞所利用，以此形成间质-肿瘤代谢共同体，促进肿瘤生长及转移。为验证该假说，本研究将从临床病理，体外星状细胞-胰腺癌细胞共培养、裸鼠原位胰腺癌模型三个方面，利用分子生物学、显微切割捕获、小动物活体成像等技术，探寻Cav-1-ROS正反馈对星状细胞代谢方式的影响，及间质-肿瘤代谢共同体形成的机制，为胰腺癌的治疗提供新依据。

传统的Warburg效应认为肿瘤细胞依赖于糖酵解将葡萄糖转化为乳酸来获取能量，即使是在常氧条件下也是如此。而近期一些临床病理研究发现，在乳腺癌组织中癌细胞并不高表达糖酵解关键酶；相反，间质细胞内存在增强的糖酵解效应。我们的研究发现将胰腺肿瘤细胞与星状细胞共培养时，星状细胞糖酵解相关酶表达量升高，同时肿瘤细胞的氧化磷酸化酶表达量升高，另外星状细胞乳酸生成增多，乳酸排出能力升高；而肿瘤细胞乳酸生成减少，摄取乳酸等能量物质的能力升高，胰腺癌中也存在肿瘤细胞与间质细胞之间的能量交流，存在细胞间的代谢共同体的形成，即共培养条件下，星状细胞的能量代谢转向有氧糖酵解，排出乳酸等能量物质，而这些能量物质为肿瘤细胞所摄取利用进行氧化磷酸化。星状细胞中存在Cav-1-ROS正反馈，即Cav-1的下调能够引起ROS水平的增高，而ROS水平的增高又能下调Cav-1的水平。而星状细胞Cav-1-ROS正反馈能够调控共培养状态下间质 - 肿瘤代谢共同体的形成。Cav-1水平的下调能够促进共培养状态下星状细胞的有氧糖酵解和肿瘤细胞的氧化磷酸化，促进代谢共同体的形成；ROS水平的下调又能抑制星状细胞的有氧糖酵解和肿瘤细胞的氧化磷酸化，从而抑制代谢共同体的形成。Cav-1-ROS正反馈能够促进皮下及原位移植瘤的生长，并且胰腺癌组织的间质中均存在不同程度的Cav-1缺失；且间质Cav-1缺失与肿瘤淋巴结转移、远处转移和TNM分期呈正相关，也是患者不良预后的独立影响因子之一。并且Cav-1的缺失与胰腺癌代谢共同体的形成相关。综上所述，我们揭示了Cav-1-ROS正反馈对星状细胞代谢方式的影响，及间质-肿瘤代谢共同体形成的机制，为胰腺癌的治疗提供新依据。