癌相关成纤维细胞对食管鳞癌CXCR7表达和活化的调控机制研究

Esophageal cancer is one of the most common gastrointestinal malignancies. Our country has a high incidence of esophageal squamous cell carcinoma (ECSS) with poor prognosis. Currently, there are no targeted treatment regimens. Our previous study found that CXCR7 plays an important role in the development of esophageal squamous cell carcinoma which may be an effective therapeutic target. However, there are few reports currently available regarding CXCR7 in ESCC. As a major component of esophageal cancer microenvironment, cancer-associated fibroblasts (CAFs) undergo elaborated and complex regulation during tumor development. We have previously shown that IL6 is the key molecule that promotes the up-regulation of CXCR7 among the soluble molecules secreted by CAF. However, after blocking IL6, the up-regulation effect of CAFs on CXCR7 was not completely inhibited. In subsequent studies, the participation of factors such as IL8 and IL10 was further excluded, and we found that the exosome of CAF also significantly increased CXCR7 expression. In addition, CAFs activates the downstream pathways of CXCR7 by promoting the secretion of SDF-1 by ESCC cells, and the specific mechanism is not yet clear. We hypothesized that CAFs plays a role in tumorigenesis and progression by regulating the CXCR7 signaling pathway in ESCC. This study is to evaluate the impact explore the mutual influence between CAFS and CXCR7, and confirm the mechanism at the levels of the molecules, cell lines, ESCC tissues and nude mice model in order to find a novel measurement and method for the treatment of ESCC.

我国食管鳞癌（ESCC）高发，预后差，尚无有效靶向治疗手段。申请人早期研究发现CXCR7在ESCC进展中具有重要作用，是有效的治疗靶点。迄今CXCR7在ESCC中研究较少，调控机制不明确。作为肿瘤微环境主要成分，癌相关成纤维(CAFs)在肿瘤发展过程中有着精细而复杂的调控作用。前期研究显示CAFs上清中IL6是促进CXCR7上调的关键分子。但阻断IL6后，CAFs上清对CXCR7的上调作用不能完全抑制，进一步排除IL8、IL10等因子的参与，我们发现CAFs分泌的外泌体在其中发挥重要作用。此外，CAFs通过促进ESCC细胞分泌SDF-1进而活化CXCR7下游通路，具体机制尚未明确。因此，我们假设CAFs通过调控CXCR7的表达和活化达到促肿瘤作用。本研究拟从分子、细胞、组织等多方面探讨CAFs与CXCR7表达和功能激活的相互影响及机制，为开发食管鳞癌治疗靶点药物提供理论依据。

食管癌是消化系统常见恶性肿瘤，河南省食管癌发病率居全国首位，因早期转移快半数以上无手术机会，化疗敏感性不高，因此预后差，且尚无有效的靶向药物。肿瘤微环境是肿瘤发生发展的关键所在，对其调控有着重要的意义。前期实验组已经挖掘肿瘤微环境主要基质细胞CAF可通过分泌IL6调控ESCC细胞CXCR7的表达促进癌症发生发展。本项目在此基础上进一步明确了CAF调控CXCR7的另一条通路，即分泌大量包裹mir137的外泌体作用于ESCC细胞抑癌基因HIC1进而促进CXCR7的上调。此外也关于CAF细胞对CXCR7的主要配体SDF-1的调控也进行了研究。通过体外孵育实验、免疫组化定位、基因敲除模型等一系列实验手段证实CAF细胞来源的FGF17作用于ESCC细胞FGFR4激活下游信号、促进FGFR4的表达及SDF-1分泌。本项目相对完整的探究了CAF细胞对ESCC细胞SDF-1/CXCR7轴的调控作用，为靶向该轴线相关基因药物的研究提供了一定的理论基础和数据支撑。