Prion Protein of Extracellular Vesicle Regulates the Progression of Colorectal Cancer

Simple Summary Cellular prion protein (PrP(C)) are overexpressed in cancers and related to cancer proliferation, invasion, metastasis, and drug resistance. The aim of our study was to investigate the role of PrP(C)-expressing exosomes regulating the colorectal cancer cells (CRC) behavior and tumor progression. We confirmed the increased sphere formation, expression of cancer initiating genes, motility, and tumor growth by hypoxic exosomes. Also, PrP(C)-expressing exosomes induced the microenvironment of metastasis via increase of endothelial permeability and angiogenic cytokine secretion. The treatment of anti-PrP(C) and 5-fluorouracil decreased the tumor progression. Targeting PrP(C) is an effective therapeutic strategy in cancer therapy. Colorectal cancer (CRC) is one of the leading causes of cancer-related death due to its aggressive metastasis in later stages. Although there is a growing interest in the tumorigenic role of cellular prion protein (PrP(C)) in the process of metastasis, the precise mechanism behind the cellular communication involving prion proteins remains poorly understood. This study found that hypoxic tumor microenvironment increased the PrP(C)-expressing exosomes from CRC, and these exosomes regulate the CRC cell behavior and tumor progression depending on the expression of PrP(C). Hypoxic exosomes from CRC cells promoted sphere formation, the expression of tumor-inducing genes, migration, invasion, and tumor growth. Furthermore, these exosomes increased endothelial permeability, migration, invasion, and angiogenic cytokine secretion. These effects were associated with PrP(C) expression. Application of anti-PrP(C) antibody with 5-fluorouracil significantly suppressed the CRC progression in a murine xenograft model. Taken together, these findings indicate that PrP-expressing exosomes secreted by hypoxic CRC cells are a key factor in the tumorigenic CRC-to-CRC and CRC-to-endothelial cell communication. Significance: These findings suggest that inhibiting PrP(C) in hypoxic exosomes during chemotherapy may be an effective therapeutic strategy in colorectal cancer.