Colorectal cancer-derived CAT1-positive extracellular vesicles alter nitric oxide metabolism in endothelial cells and promote angiogenesis

Atsushi Ikeda, Satoshi Nagayama, Makoto Sumazaki, Makoto Konishi, Risa Fujii, Naomi Saichi, Satoshi Muraoka, Daisuke Saigusa, Hideaki Shimada, Yoshiharu Sakai, Koji Ueda
2021 Molecular Cancer Research  
Accumulating scientific evidences strongly support the importance of cancer-derived extracellular vesicles (EVs) in organization of tumor microenvironment and metastatic niches, which are also considered as ideal tools for cancer liquid biopsy. To uncover the full scope of proteomic information packaged within EVs secreted directly from human colorectal cancer (CRC), we cultured surgically-resected viable tissues and obtained tissue-exudative extracellular vesicles (Te-EVs). Our quantitative
more » ... filing of 6,307 Te-EV proteins and 8,565 tissue proteins from primary CRC and adjacent normal mucosa (n = 17) allowed identification of a specific cargo in CRC-derived Te-EVs, high affinity cationic amino acid transporter 1 (CAT1, p = 5.0 × 10-3, fold change = 6.2), in addition to discovery of a new class of EV markers, VPS family proteins. The EV sandwich ELISA confirmed escalation of the EV-CAT1 level in plasma from CRC patients compared to healthy donors (n = 119, p = 3.8 × 10-7). Further metabolomic analysis revealed that CAT1-overexpressed EVs drastically enhanced vascular endothelial cell growth and tubule formation via upregulation of arginine transport and downstream nitric oxide metabolic pathway. These findings demonstrate the potency of CAT1 as an EV-based biomarker for CRC and its functional significance on tumor angiogenesis. Implications: This study provides a proteome-wide compositional dataset for viable CRC tissue-derived EVs and especially emphasizes importance of EV-CAT1 as a key regulator of angiogenesis.
doi:10.1158/1541-7786.mcr-20-0827 pmid:33579815 fatcat:j3g52x3jgbfmpgxe7kckfbseua