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

BACKGROUND: Chronic radiation injury of the intestine is associated with si gnificant underexpression of a potent physiological anticoagulant, endothel ial cell thrombomodulin (TM). This study compared early and late radiation- induced changes in endothelial TM, urokinase plasminogen activator (uPA), a nd transforming growth factor beta (TGF-beta) in normal rectum and tumors. METHODS: Rectal resection specimens from 27 patients were analyzed: Nine pa tients underwent primary resection of rectal cancer, 11 tumors were resecte d after neo-adjuvant radiotherapy, and 7 because of local recurrence after prior resection and adjuvant radiotherapy. TM, uPA, and extracellular matri x-associated TGF-beta immunoreactivity were assessed using computerized ima ge analysis. RESULTS: Multivariate analysis revealed that tumors had more TM-positive ve ssels (P = 0.003), more uPA-positive cells (P < 0.001), and higher TGF-beta immunoreactivity levels (P < 0.001) than normal rectum. Preoperative irrad iation was associated with decreased proportions of TM-positive vessels in tumors (P = 0.003) and normal rectum (P < 0.001). Irradiated tumors had few er uPA-positive cells (P = 0.003) and less TGF-beta immunoreactivity (P = 0 .001) than unirradiated tumors. The proportion of TM-positive vessels in ir radiated rectum from patients with recurrence was decreased (P = 0.03), whe reas the recurrent (ie, unirradiated) tumors did not differ from primary tu mors 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 anticoagu lant function may be a potential method to optimize the therapeutic ratio o f adjuvant radiotherapy of rectal cancer. Am J Surg. 1998;176: 642-647. (C) 1998 by Excerpta Medica, Inc.