Exosomal FGG promotes colorectal cancer liver metastases through inducing angiogenic pre-metastatic niche formation

Abstract

Angiogenesis is a defining feature of a pre-metastatic niche and is essential for primary colorectal cancer (CRC) tumor metastasis. Epithelial-mesenchymal transition (EMT) also serves as a critical driver of CRC tumor metastatic progression. Here, we hypothesized that exosomes from CRC cells promoted liver metastasis by remodeling tumor microenvironment. To verify this hypothesis, exosomes from CRC cells were isolated and identified, and the effects of these exosomes on human umbilical vein endothelial cells (HUVECs) were investigated. Exosomes from CRC cells promoted vascularization, permeability and migration of HUVECs. Mechanistically, exosomes derived from CRC cells delivered Fibrinogen gamma (FGG) to exert their effects on HUVECs. Furthermore, FGG downregulated the levels of VE-cadherin and E-cadherin in CRC cells, while upregulating N-cadherin and vimentin levels, thereby enhancing endothelial permeability and promoting EMT. In vivo experiments demonstrated that FGG downregulated VE-cadherin in CRC tissues and upregulated CD31 in liver tissues, ultimately leading to an increased number of metastatic liver nodules in a mouse model of CRC liver metastasis. In conclusion, FGG facilitates CRC liver metastasis by regulating key angiogenic, adhesion and mesenchymal markers via exosome-mediated mechanisms, resulting enhanced angiogenesis, vascular permeability, and EMT induction. These findings offer new insights into the mechanisms and treatment strategies of CRC liver metastasis.