Differential effect of radiation on endothelial cell function in rectal cancer and normal rectum

Background: Chronic radiation injury of the intestine is associated with significant underexpression of a potent physiological anticoagulant, endothelial cell thrombomodulin (TM). This study compared early and late radiation-induced changes in endothelial TM, urokinase plasminogen activator (uPA), and transforming growth factor β (TGF-β) in normal rectum and tumors. Methods: Rectal resection specimens from 27 patients were analyzed: Nine patients underwent primary resection of rectal cancer, 11 tumors were resected after neo-adjuvant radiotherapy, and 7 because of local recurrence after prior resection and adjuvant radiotherapy. TM, uPA, and extracellular matrix-associated TGF-β immunoreactivity were assessed using computerized image analysis. Results: Multivariate analysis revealed that tumors had more TM-positive vessels (P = 0.003), more uPA-positive cells (P <0.001), and higher TGF-β immunoreactivity levels (P <0.001) than normal rectum. Preoperative irradiation was associated with decreased proportions of TM-positive vessels in tumors (P = 0.003) and normal rectum (P <0.001). Irradiated tumors had fewer uPA-positive cells (P = 0.003) and less TGF-β immunoreactivity (P = 0.001) than unirradiated tumors. The proportion of TM-positive vessels in irradiated rectum from patients with recurrence was decreased (P = 0.03), whereas the recurrent (ie, unirradiated) tumors did not differ from primary tumors in terms of TM, TGF-β, or uPA immunoreactivity. Conclusions: The results support a role for endothelial dysfunction in the pathogenesis of radiation proctitis. Maintaining endothelial cell anticoagulant function may be a potential method to optimize the therapeutic ratio of adjuvant radiotherapy of rectal cancer.