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 beta (TGF-beta) 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-beta, 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-beta 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-beta 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-beta, 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.
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 beta (TGF-beta) 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-beta, 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-beta 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-beta 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-beta, 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.
Authors: Romany L Stansborough; Emma H Bateman; Noor Al-Dasooqi; Joanne M Bowen; Dorothy M K Keefe; Ann S J Yeoh; Richard M Logan; Eric E K Yeoh; Andrea M Stringer; Rachel J Gibson Journal: Support Care Cancer Date: 2017-02-07 Impact factor: 3.603
Authors: Eva Angenete; Marcus Langenskiöld; Ingrid Palmgren; Peter Falk; Tom Oresland; Marie-Louise Ivarsson Journal: Int J Colorectal Dis Date: 2007-07-27 Impact factor: 2.571