Radiotherapy reduces ATP-mediated relaxation in human rectal smooth muscle

Area of Science:

• Gastroenterology
• Oncology
• Cell Biology

Background:

• Rectal cancer radiation therapy frequently leads to long-term bowel dysfunction.
• Platelet-derived growth factor receptor alpha-positive (PDGFRα⁺) cells and interstitial cells of Cajal (ICC) are crucial for rectal smooth muscle function.
• Understanding radiation's impact on these cells and signaling pathways is vital for improving patient outcomes.

Purpose of the Study:

• To investigate how preoperative chemoradiotherapy (CCRT) affects rectal smooth muscle motility.
• To determine the role of PDGFRα⁺ cells and ICC in radiation-induced bowel dysfunction.
• To explore potential therapeutic targets for mitigating long-term bowel dysfunction after pelvic radiotherapy.

Main Methods:

• Human rectal tissues from patients with or without CCRT were analyzed.
• Isometric tension recordings assessed myogenic responses to various stimuli (KCl, ACh, SNP, ATP).
• Immunohistochemistry, quantitative PCR, and electrical field stimulation evaluated cellular and neurogenic components.

Main Results:

• Irradiated rectal tissue showed significantly reduced ATP-induced relaxation and suppression of slow wave activity.
• Expression of PDGFRα and Kit was markedly decreased in irradiated tissues.
• Immunostaining confirmed a reduction in PDGFRα⁺ cells and ICC following pelvic irradiation.

Conclusions:

• Preoperative CCRT is associated with reduced PDGFRα⁺ cells and ICC, contributing to impaired ATP-mediated inhibitory responses.
• These changes in purinergic signaling may underlie radiation-associated rectal dysmotility.
• Targeting purinergic signaling presents a potential therapeutic strategy to enhance bowel function post-radiotherapy.