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

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.

Laparoscopic Proximally Extended Colorectal Resection With Two-Stage Turnbull-Cutait Pull-Through Coloanal Anastomosis for Late Complications of Chronic Radiation Proctopathy

“…Chronic radiation proctopathy (CRP) is a common complication after radiation therapy for pelvic carcinomas, and its primary clinical manifestations are diarrhea, rectal bleeding, abdominal pain, fecal incontinence, and anal pain ( 1 , 2 ). The chronic phase of radiation proctopathy is characterized by inflammation, irreversible fibrosis, and occluding vasculitis, and platelet-derived growth factor C signaling was found to be activated in our previous study ( 3 ). Due to radiotherapy, the damaged bowel has a poor wound healing ( 4 ), which is progressive and can lead to fistula, perforation, stricture, severe bleeding and deep ulceration, severely affecting patients' quality of life ( 5 , 6 ).…”

CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis

“…We used two different animal models to elucidate the role of CXCL16 in fibrosis and epithelial repair. We employed the RE model reported by our group to study fibrosis [30], which mimics clinical radiation therapy for pelvic tumors by administering irradiation to the pelvic region of mice. After testing with different irradiation doses, the pathological changes in the rectum of mice 8 weeks after 25 Gy irradiation could recapitulate the typical features of human RE [30,43].…”

“…We employed the RE model reported by our group to study fibrosis [30], which mimics clinical radiation therapy for pelvic tumors by administering irradiation to the pelvic region of mice. After testing with different irradiation doses, the pathological changes in the rectum of mice 8 weeks after 25 Gy irradiation could recapitulate the typical features of human RE [30,43]. Since the epithelial renewal of rectum is not as fast as that of small intestine and colon, and pelvic radiation therapy sometimes inevitably causes injury to the small intestine and colon in clinical practice, we used a 12 Gy AIR model to investigate the role of CXCL16 in the epithelial repair ability of small intestine and colon in the acute phase after irradiation, which is widely used to study intestinal epithelial regeneration after injury [32,44,45].…”

“…The RE mouse model was established as described in our previous study [30]. In brief, 8‐ to 10‐week‐old mice received a dose of 25 Gy irradiation using a RS2000 X‐ray Irradiator (Rad Source Technologies, Inc., Boca Raton, FL, USA).…”

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

“…In their following experiments, the use of crenolanib, a selective agonist for PDGF receptors, in a PEG-400-based solubilizer, successfully prevented and/or ameliorated RP in mice, supported with a 20% thickness reduction of the submucosal layer and a decreased level of expression of fibrosis markers (α-SMA and fibronectin) in a mice model 8 weeks after RT. 437 Another study employed spherical polydopamine nanoparticles (PDA-NPs) at 50 mg kg −1 via an oral administration route to scavenge ROS and suppress inflammation in RT-induced intestinal injury murine models. Successfully, the content of MDA, an indicator of the lipid peroxidation of intestines, was reduced by ∼3 fold or ∼1 fold in RT + PDA-NPs on day 1 or day 3.5 post-radiation, respectively, compared to that with radiation only.…”