Cancer Exosome-derived Integrin α6 and Integrin β4 Promote Lung Metastasis of Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) metastasis remains the major cause of the CRC mortality, while the underlying mechanisms remain to be fully understood. In this study we investigated the role of cancer exosomes in CRC lung metastasis in vivo and in vitro. Methods: Expressions of Integrinα6 and Integrin β4 were examined in CRC cells as well as released exosomes. Co-culture assay with vascular endothelial cells was also analyzed.Results: We found that Integrin α6 and Integrin β4 are overexpressed in highly tumorigenic and metastatic CRC cell lines HCT116 and SW620 and their secreted exosomes, compared to the low tumorigenic and non-metastatic CRC cell lines. Disruption of ITGA6 and ITGB4 expression in CRC decreased the proliferation and tubulogenic capacities of vascular endothelial cells significantly, while ectopic expression of ITGA6 and ITGB4 gave rise to opposite effects. Further more, we demonstrated that exosomal ITGA6 and ITGB4 promoted the lung metastasis of CRCs in vivo.Conclusions: Our study provides new insight into the molecular mechanism of CRC metastasis by which CRC-derived exosomal ITGA6 and ITGB4 induce organotropism to the lung, leading to increased tubulogenic capacity and metastasis. It also reveals a biomarker-based prediction for CRC metastasis and a novel potential therapeutic targets for CRC.