结直肠癌细胞激活肝星状细胞形成肝转移前微环境促进肝转移的作用及分子机制研究

Pre-metastatic niche is a favorable microenvironment in secondary organs and tissue sites for subsequent tumor metastasis. Liver is the most common metastatic organ for colorectal carcinoma. However, the function and mechanism on colorectal carcinoma creates a pre-metastatic niche to promote liver metastasis is still far from clear. Hepatic stellate cells （HSC） is the main stroma cells in liver. Our preliminary results had shown that HSC was activated in liver with liver metastases of colorectal carcinoma, and the quantity of HSC increased with the progress of metastasis. Therefore, we speculated that colorectal carcinoma cells create a pre-metastatic niche to promote liver metastasis through activation of HSC in liver. We had demonstrated that mesenchymal-like colorectal carcinoma cells activated HSC to promote liver metastasis by forming a pre-metastatic niche via secreting IGF-1. Based on preliminary research, we plan to use ELISA, immunofluorescence (IF), cell co-culture, lentiviral vector transfection, IVIS xenogen technique and in situ colorectal cancer model in nude mice et al. to verify that colorectal carcinoma cells activate HSC to create a favorable microenvironment via secreting IGF-1 and its role in promoting liver metastasis. And then, assays including RayBio Human Cytokine Antibody Array, gene knock-out mouse model et al. were used to screen and verify the target signal pathway of IGF-1. These results were further confirmed in human samples. Through present study, we will clarify the mechanism on colorectal carcinoma cells create a pre-metastatic niche to promote liver metastasis via activation of hepatic stellate cells. And it will provide important theorectical basis in preventing liver metastases of colorectal carcinoma.

转移前微环境在肿瘤器官转移中起促进作用。肝脏是结直肠癌最常见的转移器官，而目前结直肠癌细胞改造、形成肝转移前微环境促进肝转移的作用机制尚知之甚少。肝星状细胞（HSC）是肝脏内最主要的间质细胞，前期研究显示结直肠癌肝转移的肝组织中HSC被激活，且HSC活化数量随着转移进展而增加。故我们推测结直肠癌细胞可激活HSC形成转移前微环境促进肝转移。我们已证实间质细胞样的结直肠癌细胞分泌IGF-1激活HSC。本研究结合前期研究，拟用ELISA、IF、细胞共培养、慢病毒转染、小动物活体成像技术与裸鼠原位结直肠癌模型等探索结直肠癌细胞分泌IGF-1激活HSC形成转移前微环境促进肝转移的作用。继而结合文献，利用细胞因子抗体蛋白芯片、基因敲除鼠等体外、内试验筛选与验证作用信号通路，并用临床样本验证，阐明结直肠癌细胞激活HSC形成转移前微环境促进肝转移的分子机制，为研发预防肝转移的新策略奠定坚实的理论基础。

转移前微环境在肿瘤器官转移中起促进作用。肝脏是结直肠癌最常见的转移器官，而目前结直肠癌细胞改造、形成肝转移前微环境促进肝转移的作用机制尚知之甚少。肝星状细胞（HSC）是肝脏内最主要的间质细胞，我们研究结果显示结直肠癌肝转移的肝组织中HSC被激活，且HSC活化数量随着转移进展而增加。结直肠癌细胞可激活HSC形成转移前微环境促进肝转移，业已证实结直肠癌细胞分泌CCL-2激活HSC促进肝转移。且机制研究进一步证实CCL-2通过调控FAK通路激活HSC形成转移前微环境。本研究阐明了结直肠癌细胞分泌CCL-2激活HSC形成转移前微环境促进肝转移的作用，为研发预防肝转移的新策略奠定坚实的理论基础。