Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy

• Published in: Science translational medicine Vol. 13; no. 582
• Main Authors: Lu, Weisi, Xie, Yunling, Huang, Binjie, Ma, Tenghui, Wang, Huaiming, Deng, Boxiong, Zou, Shaomin, Wang, Wencong, Tang, Qin, Yang, Ziqing, Li, Xuri, Wang, Lei, Fang, Lekun
• Format: Journal Article
• Language: English
• Published: United States 24-02-2021
• Subjects: Animals; Humans; Lymphokines; Mice; Platelet-Derived Growth Factor; Radiation Injuries - therapy; Receptors, Platelet-Derived Growth Factor - metabolism; Rectum - pathology; Rectum - radiation effects; Signal Transduction
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.abc2344

Radiation proctopathy (RP) is characterized by inflammation of colorectal tissue and is a common complication of radiation therapy for pelvic malignancies with high incidence but lacking effective treatment. Here, we found that platelet-derived growth factor C (PDGF-C) and fibrosis markers were up-regulated in tissue samples from patients with RP and in rectal tissues after irradiation in a mouse model of RP. Genetic deletion of
in mice ameliorated RP-induced injuries. Genome-wide gene expression profiling and in vitro assays revealed that the promotive effect of PDGF-C in RP development was mediated by activation of PDGF receptors (PDGFRs) and C-X-C motif chemokine receptor 4, a proinflammatory chemokine regulated by transcription factor ETS variant transcription factor 1. Treatment with crenolanib, a selective inhibitor of PDGFRs, prevented or reduced RP in mice after irradiation. These results reveal that inhibition of PDGF-C signaling may have therapeutic value for the treatment of RP.