血管内皮细胞纤维粘连蛋白EDA片段诱导结肠癌细胞上皮间质转化的作用及机制研究

Tumor microenvironment plays an important role in tumor pathogenesis, but the effect of tumor blood vessel endothelial cells on tumor cells remains elusive. We have demonstrated in our youth grant that fibronectin extra domain A sustains the stemness of colon cancer cells via interacting with its receptor integrinα9β1, and identified that the integrinα9β1 positive colon cancer cells are mainly located around the blood vessels。EDA of endothelial cells were found to play a chemotactic effect on integrinα9β1 positive colon cancer cells and induce an epithelial-mesenchymal transition(EMT). We also proposed that FAK/Src/snail pathway may be potentially involved in EDA induced EMT. This project aims to further investigate the effect and the mechanism of EDA on EMT of colon cancer cells, and the outcome will further reveal the effect of tumor microenvironment on tumor pathogenesis and indicate a new target for colon cancer targeting therapy.

肿瘤微环境对肿瘤生物学特性发挥重要作用，但肿瘤血管内皮细胞对肿瘤细胞的影响尚不明确。我们在青年基金项目中已证实结肠癌基质成分纤维粘连蛋白EDA片段通过其受体整合素α9β1促进结肠癌细胞"干性"维持，进一步研究发现整合素α9β1阳性的结肠癌细胞聚集在肿瘤血管周围，而血管内皮细胞表达的EDA而对其发生明显的趋化作用，并可诱导整合素α9β1阳性结肠癌细胞发生上皮间质转化（EMT)，结合EDA-整合素α9β1和EMT通路的关联推测：EDA-整合素α9β1通过激活FAK/Src/snail通路对诱导结肠癌细胞EMT发挥重要作用。本项目拟建立血管内皮细胞EDA敲除小鼠及慢病毒建立EDA过表达及低表达血管内皮细胞模型，通过体内外实验观察血管EDA诱导结肠癌细胞EMT的效应，并阐明EDA诱导结肠癌细胞EMT发生的具体分子机制，为针对结肠癌转移的靶向治疗寻找到新的靶点。

肿瘤微环境对肿瘤生物学特性发挥重要作用，但肿瘤血管内皮细胞对肿瘤细胞的影响尚不明确。我们在青年基金项目中已证实结肠癌基质成分纤维粘连蛋白EDA片段通过其受体整合素α9β1促进结肠癌细胞"干性"维持，进一步研究发现整合素α9β1阳性的结肠癌细胞聚集在肿瘤血管周围，而血管内皮细胞表达的EDA而对其发生明显的趋化作用，并可诱导整合素α9β1阳性结肠癌细胞发生上皮间质转化（EMT)，结合EDA-整合素α9β1和EMT通路的关联推测：EDA-整合素α9β1通过激活FAK/Src/snail通路对诱导结肠癌细胞EMT发挥重要作用。本项目拟建立血管内皮细胞EDA敲除小鼠及慢病毒建立EDA过表达及低表达血管内皮细胞模型，通过体内外实验观察血管EDA诱导结肠癌细胞EMT的效应，并阐明EDA诱导结肠癌细胞EMT发生的具体分子机制，为针对结肠癌转移的靶向治疗寻找到新的靶点。