Suppression of Fas expression and down-regulation of Fas ligand in highly aggressive human thyroid carcinoma

The Fas-FasL system seems to mediate thyrocyte death in Hashimoto's thyroid itis. In thyroid cancer, downregulation of bcl-2 seems to alter apoptosis c ontrol. We compared the expression of immunoreactive Fas and FasL in normal thyroid with that of tumors ranging from benign to highly aggressive. Fas is essentially not expressed in normal thyrocytes, whereas FasL is expresse d in approximately one-third of cases. Expression of both markers is signif icantly up-regulated in adenoma and in well-differentiated papillary and fo llicular carcinoma. In contrast, Fas is suppressed and FasL is strongly red uced in the most aggressive histological variants (poorly differentiated an d undifferentiated carcinoma). Immunohistochemistry findings have been conf irmed by analysis of Fas-FasL mRNA transcripts. In vitro studies showed tha t the Fas receptor of thyroid tumor cells was functional, because apoptosis was induced by an agonistic Fas antibody. Fas-expressing and Fas-resistant mammary cell lines were used as specificity controls. Together with our pr evious data inversely relating bcl-2 expression and thyroid tumor grade, th e present findings further indicate that apoptotic pathways are altered in thyroid neoplasia. Thus, the Fas-FasL system may represent a marker of tumo r aggressiveness.