Angiogenesis is promoted by exosomal DPP4 derived from 5-fluorouracil-resistant colon cancer cells

• Published in: Cancer letters 2021-01, Vol.497, p.190-201
• Main Authors: Zheng, Xixi, Liu, Juan, Li, Xiao, Tian, Ruyue, Shang, Kun, Dong, Xin, Cao, Bangwei
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; 5-FU resistance; Angiogenesis; Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer therapies; Case-Control Studies; Cell adhesion & migration; Cell Proliferation; Chemotherapy; Colon cancer; Colonic Neoplasms - blood supply; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Dipeptidyl Peptidase 4 - genetics; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-peptidase IV; DPP4; Drug resistance; Drug Resistance, Neoplasm; Endothelial cells; Exosomes; Exosomes - metabolism; Fluorouracil - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Male; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Nuclear transport; Peptidase; Prognosis; Proteins; Roles; Signal transduction; Smad protein; Transmission electron microscopy; Tumor cells; Tumor Cells, Cultured; Tumor Microenvironment; Umbilical vein; Vascular endothelial growth factor; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.10.009

Cancer cells can communicate with the tumor microenvironment and contribute to tumor progression. However, the effects of drug-resistant tumor cells on angiogenesis are unclear. Current anti-angiogenic strategies also have limitations and it would be useful to develop novel targets and treatment strategies. Here, our study showed that the conditioned medium and exosomes from 5-FU-resistant colon cancer cells promoted angiogenesis, and we observed that exosomal dipeptidyl peptidase IV (DPP4) was a potent inducer of this angiogenesis. DPP4-enriched exosomes increased periostin (POSTN) expression in human umbilical vein endothelial cells via Twist1 nuclear translocation or activating Smad signaling pathway, while silencing or inhibition of DPP4 neutralized those effects. The in vivo and clinical data indicated that high DPP4 expression was related to tumor progression. These findings indicate that DPP4 may be a target for inhibiting angiogenesis in 5-FU-resistant colon cancer. Furthermore, exosomal DPP4 concentrations may be a useful prognostic marker for colon cancer. •Exosomes derived from HCT-8/FU cells accelerated angiogenesis.•Exosomal DPP4 was a potent inducer of angiogenesis by elevating POSTN level.•DPP4 promoted in vivo tumor progression and low differentiation.