Exosomes Derived From Hypoxic Colorectal Cancer Cells Promote Angiogenesis Through Wnt4-Induced β-Catenin Signaling in Endothelial Cells

Cancer cell-derived exosomes have been actively released into the tumor microenvironment with pleiotropic roles in tumor growth and metastasis, including angiogenesis and immune modulation. However, the functions and underlying mechanisms of exosomes shed by colorectal cancer (CRC) cells under hypoxic conditions remain unknown. Here we found that exosomes derived from hypoxic CRC cells promoted the proliferation and migration of endothelial cells. Suppression of exosome secretion through RAB27a knockdown in CRC cells inhibited exosomal-induced proliferation and migration of endothelial cells. Furthermore, we discovered that these exosomes enriched with Wnt4 were dependent on HIF1α. Exosomal Wnt4 increased β-catenin nuclear translocation in endothelial cells. The induction of β-catenin signaling is critical for the proliferation and migration of endothelial cells, which could be abolished by the inhibitor ICG001. The in vivo animal study further revealed the tumor-promoting effects of CRC cell-derived exosomes with enhanced tumor growth and angiogenesis. Taken together, our study indicates that CRC cells promote angiogenesis through exosome-mediated Wnt/β-catenin signaling in endothelial cells under hypoxia, which might be a new mechanism in CRC development.