肿瘤微环境中成纤维细胞自噬对膀胱癌糖代谢及恶性潜能的影响

项目名称： 肿瘤微环境中成纤维细胞自噬对膀胱癌糖代谢及恶性潜能的影响

项目编号： No.81672512

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 孙立江

作者单位： 青岛大学

项目金额： 25万元

中文摘要： 肿瘤微环境和自噬是肿瘤领域的研究热点，而自噬对微环境中细胞代谢的影响研究较少。我们前期观察到共培养环境中成纤维细胞（hFF）可转化为肿瘤相关成纤维细胞，其单羧酸转运体MCT的表达上调，微环境中乳酸水平升高；抑制hFF的MCT表达可抑制膀胱癌细胞增殖和侵袭，诱导其凋亡，同时hFF自噬水平升高，该信号通路重要分子p62可与MCT相互作用，推断hFF自噬可能参与了膀胱癌的发生发展，尤其对细胞糖代谢产生影响。基于此假说，我们拟通过构建3D细胞共培养体系，采用分子克隆、药物干预、裸鼠成瘤实验等手段，通过改变微环境中hFF的自噬水平，从分子、细胞、体外和体内探讨hFF是否通过自噬-p62-MCT通路调节微环境乳酸水平，并进一步影响膀胱癌细胞糖代谢及生物学表型。本研究从肿瘤微环境中hFF自噬对微环境及膀胱癌糖代谢及生物学表型的作用这个新的视角出发，为揭示膀胱癌发病机制、探索临床可行治疗靶点提供新依据。

中文关键词： 膀胱肿瘤；肿瘤微环境；自噬；成纤维细胞

英文摘要： Recent studies have focused on the relationship between tumor microenvironment, autophagy and carcinogenesis. However, little is known about the role of autophagy in a tumor microenvironment in tumor metabolism, and its underlying mechanisms. .Our previous researches have observed that fibroblasts could transformed into cancer-associated fibroblasts (CAFs) in a vivo-like microenvironment, accompanied with up-regulated expression of Monocarboxylate anion transporters (MCT) and enhanced autophagy, as well as elevated lactate levels in the tumor microenvironment. MCT inhibition of CAFs could suppress bladder cancer T24 cell proliferation and invasion, and induce cell apoptosis. In addition, we observed an interaction between p62 and MCT. Based on these results, we hypothesize that autophagy in CAFs might play a role in the development of bladder cancer in the tumor microenvironment, where glucose metabolism change might be involved. Consequently, we aim to understand whether CAFs can affect MCT expression and lactate levels, and subsequent glucose metabolism and biological behaviors of bladder tumor cells in the tumor microenvironment through autophagy, by means of 3-dimensional microfluidic co-culture device, lentivirus infection, pharmacological interventions, nude mouse tumorigenicity assay, et al. Finally, we would like to reveal the detailed role of autophagy in carcinogenesis from a new perspective of how autophagy takes effect on tumor in the microenvironment, and provide evidence of potential therapeutic targets.

英文关键词： bladder tumor;tumor microenvironment;autophagy;fibroblast