FGFR2阳性的癌相关成纤维细胞分泌的LTBP2在食管癌中的作用及机制研究

我们最近研究证明食管癌细胞通过分泌FGF2，从骨髓招募FGFR2阳性的循环纤维细胞（CFs），而CFs到达肿瘤组织后，通过与肿瘤细胞直接接触，分化为FGFR2阳性的癌相关成纤维细胞（CAFs），从而促进肿瘤细胞增殖、侵袭和转移。我们应用高通量转录组测序检测了10对FGFR2阳性的食管癌CAF和CF，发现潜在转化生长因子β结合蛋白2（LTBP2）特异地在CAFs中高表达，在CFs、食管癌细胞、正常成纤维细胞中表达很低。前期的实验初步证明LTBP2促进食管癌细胞平板克隆形成、转移和抑制凋亡。本项目将（1）明确LTBP2对食管癌细胞增殖、转移、化疗抵抗、干细胞干性的作用；（2）揭示LTBP2的受体及调控的下游信号通路；（3）解析LTBP2对肿瘤组织血管生成的影响及分子机制；（4）评价靶向LTBP2的中和抗体用于治疗食管癌的可行性。本课题旨在为抗食管癌药物的研发提供新靶点。

Our recent study finds that cancer associated fibroblasts (CAFs) in esophageal squamous cell carcinoma (ESCC) are FGFR2-positive cells, which can provide cancer cells with a suitable microenvironment. Interestingly, FGFR2-positive circulating fibrocytes (CFs) were recruited to the tumor environment by ESCC cells and differentiated to FGFR2-positive CAFs. To identify the difference between circulating FGFR2-positive CFs and FGFR2-positive CAFs in tumor tissue, high-throughout transcriptome sequencing (RNA-Seq) was performed on ten pairs of circulating FGFR2-positive CFs from peripheral blood and FGFR2-positive CAFs from tumor tissue. About 1016 upregulated genes were identified including latent transforming growth factor-β binding protein 2 (LTBP2). Our preliminary work demonstrates that LTBP2 can promote foci formation and cell metastasis, and suppress ESCC cells apoptosis. In this proposal, we aim to: (1) investigate the roles of LTBP2 in the proliferation, metastasis and chemo-resistant of ESCC; (2) determine the receptor and signaling pathways that mediate LTBP2 effects; (3) explore the effects of LTBP2 on tumor angiogenesis in ESCC; and (4) test the therapeutic potential of anti-LTBP2 antibody in ESCC. In summary, the new knowledge gained from this study will greatly facilitate our knowledge of characteristics and the molecular mechanism of tumor microenvironment in ESCC and develop a novel therapeutic method approach targeting on ESCC.