Transforming growth factor alpha immunoreactivity in human gallbladder and extrahepatic biliary tract tumours

Abstract

Transforming growth factor alpha (TGF-alpha), a protein structurally similar to epidermal growth factor (EGF), is implicated in the development of many human tumours. This study examines the expression of TGF-alpha in gallbladder and extrahepatic biliary tract tumours in which EGFR expression has been previously shown to be important. A monoclonal antibody to the TGF-alpha protein was used to investigate the immunohistochemical expression of TGF-alpha in carcinoma of the gallbladder (n = 13), common bile duct (CBD) (n = 6) and ampulla of Vater (n = 8). Tissues from cases of chronic cholecystitis (n = 11), gallbladder dysplasia (n = 3) and adenoma (n = 1), and ampullary carcinoma in situ (CIS) (n = 3) were used as non-malignant controls. These cases were previously studied for EGFR expression. TGF-alpha overexpression, defined as intense immunoreactivity in more than two-thirds of cells immunostained for TGF-alpha, was present in most gallbladder carcinomas (n = 10; 77%) but with no significant differences in expression between different tumour grades. None of the cases of gallbladder dysplasia or chronic cholecystitis had strong TGF-alpha expression and this was significantly different from the carcinomas (P = 0.013 and P = 0.0001, respectively; chi 2 test), although a few cases of chronic cholecystitis showed weak (n = 4), moderate (n = 6) or no (n = 1) immunoreactivity. A few ampullary carcinomas (n = 2; 25%) and CIS (n = 1; 33%), and half of the CBD carcinomas (50%) had strong TGF-alpha immunoreactivity. There was correlation between TGF-alpha and EGFR immunoreactivity in the tumour cases (r = 0.70, r2 = 0.49, P = 0.0001; simple regression analysis), although the rate of EGFR immunoreactivity in CBD and ampullary carcinomas was somewhat higher than that of TGF-alpha. However, no statistically significant correlation between TGF-alpha expression with patient survival or tumour recurrence (r = 0.11, r2 = 0.012, P = 0.65; simple regression analysis) was found. Increased TGF-alpha expression occurs more frequently in gallbladder carcinoma than in gallbladder dysplasia, chronic cholecystitis, CBD or ampullary tumour, with no specific relationship to tumour grade, suggesting that TGF-alpha overexpression occurs early in the development of gallbladder cancers, and that biliary tract cancers have a different molecular origin. Correlation was found between TGF-alpha and EFGR expression in gallbladder and biliary tract tumours.