Research ArticleGASTROINTESTINAL DISORDERS

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

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Science Translational Medicine  24 Feb 2021:
Vol. 13, Issue 582, eabc2344
DOI: 10.1126/scitranslmed.abc2344

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Guarding the gut

Patients who undergo radiation for cancers in the pelvis can experience radiation proctopathy (RP) or inflammation of colorectal tissue. Lu et al. investigated the role of platelet-derived growth factor C (PDGF-C) in RP. Using a mouse model of RP induced by irradiation of the pelvic region, the authors found up-regulation of PDGF-C in colorectal tissue, whereas mice deficient in Pdgf-c were largely protected from lesions. Colorectal tissue samples from patients with RP also showed up-regulation of PDGF-C and fibrosis, which PDGF-C promoted via CXCR4 signaling. Administering the PDGF receptor inhibitor crenolanib reduced RP in mice, identifying a potential therapeutic target for RP.

Abstract

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 Pdgf-c 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.

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