癌相关性成纤维细胞自噬作用对胃癌转移的影响及其机制的研究

项目名称： 癌相关性成纤维细胞自噬作用对胃癌转移的影响及其机制的研究

项目编号： No.81201615

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 车晓芳

作者单位： 中国医科大学

项目金额： 23万元

中文摘要： 肿瘤转移是导致胃癌预后不良的主要原因。肿瘤微环境基质细胞中的癌相关成纤维细胞（CAF）对肿瘤的侵袭和转移起着重要的促进作用。成纤维细胞在缺氧或肿瘤细胞分泌的因子刺激下转化为CAF。CAF可刺激相邻的肿瘤细胞生长，血管新生及转移。最新研究表明，肿瘤细胞可诱导邻接CAF的HIF-1α高表达和自噬，而CAF通过自噬产生的氨基酸，脂肪酸及核苷能为相邻肿瘤细胞提供能量，维持和促进肿瘤细胞生长。但是，CAF自噬作用对邻接肿瘤细胞的侵袭和迁移的影响尚不清楚。我们的研究显示成纤维细胞HEL在低氧状态下活化并发生自噬，且VEGF，PGIS，PDGF等因子表达升高。本研究拟通过成纤维细胞与胃癌细胞共培养，建立自噬性肿瘤基质的细胞模型及自噬性肿瘤基质的胃癌动物模型，探讨CAF的自噬作用对胃癌细胞侵袭及迁移功能的作用及其机制，研究结果可为明确自噬CAF调控胃癌转移的机制及治疗方法的开发提供重要依据。

中文关键词： 癌相关成纤维细胞；CXCL12；c-met；上皮间质转化；转移

英文摘要： Gastric cancer is the second leading cause of cancer death in our country for its poor prognosis. Tumor cell metastasis is one of the major obstacles in the way of gastric cancer therapy. Tumor metastasis is determined not only by tumor cells themselves but also by stromal cells, especially the cancer-associated fibroblast (CAF) around the tumor hypoxic microenvironment. Tumor cells were interacted with CAF in a paracrine or incretion manner. It has become clear that fibroblast was induced into CAF in hypoxia or the factors such as IL-1, TGFβ, PDGF secreted by the tumor cells. Otherwise, the secretion of SDF-1, VEGF, TGF-β, PDGF, MMP2, MMP9 from CAF could promote the tumor growth, angiogenesis, invasion and metastasis. Recently, a new paradigm "The Autophagic Tumor Stroma Model of Cancer." was proposed. In this model, breast cancer cells induce the generation of ROS, stable expression of HIF-1 α, activation of NF-κB in adjacent CAF. Oxidative stress in the CAF activates an autophagic program, and the degradation of caveolin-1(cav-1) leading to the production of recycled nutrients such as amino acid, fatty acid, nucleotide that can then be used as "fuel" to promote the anabolic growth and aggressive progression of tumor epithelial cells. The caveolar marker protein cav-1 plays a role in the tumor cell migration.

英文关键词： cancer-associated fibroblast；CXCL12；c-met；EMT；metastasis