Tip-DC促大肠癌肝转移的机制研究

Myeloid cells are closely involved in the progression and metastasis of malignancies. Our previous study shows for the first time, that a unique population of myeloid cells- TNF-α/iNOS producing dendritic cells (Tip-DCs) plays pivotal roles in the progression of colorectal hepatic metastases, selective depletion of Tip-DCs leads to regression or even disappearance of established metastatic foci, and same population infiltrates in the clinical human samples of colorectal hepatic metastases. The targeting cell types and the pro-metastatic mechanisms of Tip-DCs remain unknown. In this project, based on the metastatic liver cancer mouse model and the selective depletion of Tip-DCs, which have been established in our previous work, we plan to search the targeting cell types and pathways regulated by Tip-DCs via FACS (Fluorescence-activated cell sorting) and PCR array, then validate and elucidate the pro-hepatic metastasis mechanisms of Tip-DCs and the key pathways and genes involved, to explore the new targets for therapeutic consideration and improve the prognosis of colorectal cancer.

髓系细胞（myeloid cells）在恶性肿瘤进展及转移中具有重要作用。我们前期在动物模型中发现，一种特殊的髓系细胞群"分泌TNF- α与iNOS的树突状细胞"（TNF-α/iNOS producing dendritic cells，Tip-DCs）对大肠癌肝转移灶的进展具有关键作用，选择性去除Tip-DCs可使已形成的转移灶缩小以至消失；继而在临床大肠癌患者的肝转移灶中也发现Tip-DCs的浸润。Tip-DCs所作用于的靶细胞及其促肝转移的具体机制尚不清楚。本课题拟利用已建立的肝转移及Tip-DCs选择性去除动物模型，通过流式细胞分选、PCR array技术研究Tip-DCs所作用的靶细胞，筛选受其调控的细胞信号通路，进而通过功能实验验证并阐明Tip-DCs促进大肠癌肝转移进展的具体机制，及涉及的关键信号通路与分子，以期发现具有临床价值的新的治疗靶点，从而提高大肠癌的临床治疗效果。

髓系细胞（myeloid cells）在恶性肿瘤进展及转移中具有重要作用。我们前期在动物模型中发现，CD11b+/Gr1mid髓系细胞群亚群对大肠癌肝转移灶的进展具有关键作用，选择性去除该亚群细胞可使已形成的转移灶缩小以至消失，继而在临床结直肠癌患者的肝转移灶中也发现类似亚群细胞的浸润。本研究利用已建立的动物模型，初步证明CD11b+/Gr1mid髓系细胞群亚群对转移灶的支持机制与促血管生成相关，其效应分子可能为FGF2。目前实验在结直肠癌临床标本中进行验证。本研究初步阐明了特定髓系细胞亚群促进大肠癌肝转移进展的具体机制，以及涉及的可能的关键靶分子；对发现具有临床价值的新的治疗靶点，从而提高大肠癌的临床治疗效果具有一定的指导意义。