结直肠癌FGA介导血管新生形成肝转移前微环境促进肝转移的作用及分子机制研究

肝转移是结直肠癌（CRC）主要死亡原因，转移前微环境（PMN）在CRC肝转移中起着至关重要的作用。血管新生是PMN的重要特征，靶向血管新生PMN形成有助于在CRC发生肝转移前极早进行干预和治疗，而有关CRC肝转移PMN中血管新生的机制所知甚少。前期研究证实CRC分泌的FGA与肝转移及其不良预后密切相关，且与血管新生有关。本研究拟在前期基础上，采用体外小管形成、细胞共培养、慢病毒转染、小动物活体荧光成像、基因敲除鼠和裸鼠原位CRC模型等一系列体外、体内实验阐明“FGA介导血管新生形成肝脏PMN从而促进肝转移的作用”并探索相关分子机制，发现预测血管新生PMN形成和肝转移发生的特异性分子标志物，结合临床样本探索其在临床中的意义，为研发预防和阻止CRC肝转移的新策略提供重要的理论依据。

Liver metastasis is the main cause of death in colorectal cancer (CRC). Pre-metastatic niche (PMN), a favorable microenvironment for cancer cells colonization at distant organ, plays a pivotal role in CRC liver metastases (CRCLM). Angiogenesis is one of the main characteristics that defines PMN formation. Targeting angiogenic PMN formation helps to early prevent the occurrence of liver metastases, however, the mechanism of an angiogenic PMN formation in CRCLM remains unclear. Our previous study, based on the biological information analysis of CRC transcriptomic data and a series of validation experiments combing various samples with clinical data, showed that fibrinogen alpha chain (FGA) is related to liver metastasis and participates in biological functions associated with angiogenesis. In this study, we aim to clarify that CRC-derived FGA induce the formation of an angiogenic PMN to facilitate CRCLM by using tubule formation, cell co-culture, lentiviral transfection, small animal in vivo fluorescence imaging, gene knock-out mice and CRC nude mouse models. Additionally, we aim to explore the mechanisms of angiogenic PMN formation induced by FGA and develop new specific biomarkers for diagnosis and prediction of angiogenic PMN formation and liver metastases, which will provide important theoretical basis for developing new strategies to prevent CRCLM.