食管癌旁分泌BMP7通过与成纤维细胞内Notch信号协同作用调控肿瘤微环境的研究

Tumorigenesis and tumor progression are closely associated with tumor microenvironment. Cancer associated fibroblasts (CAF) are one of the most abundant stromal cell types and play critical role in tumorigenesis and tumor progression, but the mechanisms involved in this process still need further investigation. In our previous study, we found that CAF are associated with prognosis of esophageal squamous cell carcinoma (ESCC). The receptors of BMP7 are expressed on both NF and CAF, and the expressions of Notch downstream genes in CAF are higher than that of NF. We also found that BMP7 expression is associated with lymph node metastasis and prognosis of ESCC. The expression of BMP7 is higher in ESCC cell lines with highly metastatic capacity than that without metastatic capacity, and BMP7 plays important role in invasion and migration of ESCC cell lines with highly metastatic capacity, and this effect could be blocked by BMP7 siRNA. These imply that BMP7 secreted by ESCC could act on NF or CAF through paracrine pattern, and regulate the microenvironment of ESCC through cooperation with Notch signaling in NF or CAF. Based on previous results, we plan to analyze the roles of BMP7 and Notch signaling on the functional regulation of fibroblast and formation of tumor microenvironment, and investigate the interaction between BMP7 and Notch signaling. The present study will provide new insights in the interaction between CAF and ESCC in the tumor microenvironment.

肿瘤发生进展与微环境密切相关。肿瘤相关成纤维细胞（CAF）是微环境中数量较多的间质细胞并在肿瘤进展中发挥重要作用，但其核心作用仍需深入研究。申请人前期研究表明，CAF与食管癌预后相关。食管癌中正常成纤维细胞（NF）和CAF均表达BMP7受体，且CAF的Notch靶基因表达显著高于NF。我们还发现，BMP7与食管癌淋巴结转移相关，是预后不良独立危险因素。BMP7在高转移潜能食管癌细胞系有更高表达且促进其侵袭转移，而下调BMP7可抑制该现象。强烈提示，食管癌表达的BMP7可能以旁分泌作用于NF或CAF，通过与Notch协同作用而调控其功能，最终改变食管癌微环境并促进其进展。本项目拟在前期研究基础上，分析BMP7和Notch在CAF对肿瘤微环境的构成及食管癌进展中的作用，探索BMP7和Notch是否存在相互作用及机制。本研究可为深入理解微环境中食管癌与CAF间的相互作用提供新的实验室证据。

肿瘤发生进展与微环境密切相关。肿瘤相关成纤维细胞（CAF）是微环境中数量较多的间质细胞并在肿瘤进展中发挥重要作用，但其核心作用仍需深入研究。我们前期研究发现，食管癌中正常成纤维细胞（NF）和CAF均表达BMP7受体，且CAF的Notch靶基因表达显著高于NF。我们还发现，BMP7与食管癌淋巴结转移相关，是预后不良独立危险因素。BMP7在高转移潜能食管癌细胞系有更高表达且促进其侵袭转移，而下调BMP7可抑制该现象。强烈提示，食管癌表达的BMP7可能以旁分泌作用于NF或CAF，通过与Notch协同作用而调控其功能，最终改变食管癌微环境并促进其进展。本项目拟在前期研究基础上，分析BMP7和Notch在CAF对肿瘤微环境的构成及食管癌进展中的作用，探索BMP7和Notch是否存在相互作用及机制。本研究可为深入理解微环境中食管癌与CAF间的相互作用提供新的实验室证据。我们发现食管癌组织和食管癌细胞系均能表达BMP7，且不同的食管癌组织和食管癌细胞系表达的BMP7量有差异。CAF特异性标志物α-SMA在ESCC组织中的表达强度是ESCC的独立预后因素，高表达α-SMA提示患者预后不良。同时，α-SMA蛋白的表达与ESCC患者肿瘤大小、肿瘤浸润深度以及神经侵犯相关。高表达BMP7的食管癌细胞系KYSE-150、EC9706能够在体内和体外促进NF转化为CAF，而低表达BMP7的食管癌细胞系EC109则不能将NF转化为CAF。最后活化的CAF可以进一步促进食管癌细胞系KYSE-150、EC109的增殖。