Horizontal transfer of exosomal CXCR4 promotes murine hepatocarcinoma cell migration, invasion and lymphangiogenesis

Exosomes have been demonstrated as an important factor to influence cancer invasion and metastasis. Previous studies have shown that CXC chemokine recepter-4 (CXCR4) and stromal cell-derived factor-1 alpha (SDF-1 alpha) mediates matrix metalloproteinases (MMPs) secretions to facilitate lymph node metastasis of hepatocarcinoma cells. In this study, we demonstrated that exosomes containing elevated CXCR4 from high lymph node metastatic mouse hepatocarcinoma Hca-F cells were able to promote the migration and invasion of a paired syngeneic Hca-P cells that have low metastatic potential. Such impact on enhanced migratory and invasive capacities of Hca-P cells was triggered by the internalization of exosomes isolated from Hca-F cells. This was possibly due to the horizontal transferring of CXCR4 via exosomes. The lymphatic endothelial cells (LECs) increased the migration and invasion of Hca-F cells probably by expressing SDF-1 alpha which bound with CXCR4 in the Hca-F cells and subsequently enhanced the secretions of MMP-9, MMP-2 and vascular endothelial growth factor C (VEGF-C). Exosomal CXCR4 from Hca-F cells promoted LECs proliferative rate and lymphatic tube formation ability. Our findings suggest that horizontal transfer of exosomal CXCR4 can promote murine hepatocarcinoma cell migration, invasion and lymphangiogenesis, and exosomal CXCR4 might be a novel therapeutic target against tumor lymphatic metastasis.