Die Down-Regulation von FAS (APO-1/CD95) begünstigt die Metastasierung beim Ösophaguskarzinom

Abstract

The cell surface receptor Fas (APO-1/CD95) mediates apoptosis via interaction with its ligand (FasL). Fas is normally expressed in a variety of adult tissues including epithelial tissue, whereas FasL expression is predominantly restricted to cells of the immune system or immunoprivileged tissues. In tumors, modulation of Fas and FasL expression is frequent. There is evidence that tumors may escape from immune surveillance via downregulation of Fas or expression of soluble FasL. Furthermore, upregulation of FasL on tumor cells may induce apoptosis in tumor infiltrating cytotoxic T-cells (counter attack model). So far, little is known about the role of Fas and FasL expression in the progression of esophageal carcinoma. We therefore analyzed cytostat sections of 70 esophageal carcinomas with tumor-free resection margins (Ro) for Fas and FasL expression immunohistochemically with the ABC technique using the monoclonal anti-Fas antibody DX2 (Pharmingen) and the polyclonal anti-FasL antibody Q20 (Santa Cruz Biotech.). Stained sections were evaluated semiquantitatively. Staining intensity was also taken into account. In total, 49 of 70 (70%) tumors showed downregulation of Fas, whereas upregulation of FasL was observed in 55 of 70 (79%) cases. Correlation of Fas data with nodal microdissemination status revealed that patients with Fas downregulation of their primary tumors showed isolated tumor cells in apparently “tumor free” lymph nodes more frequently than patients with normal Fas expression (60% vs. 23%; p = 0.01). Moreover, 46% of patients with Fas downregulation developed metastatic relapse within a mean time of 33 month compared to 8% of patients with normal Fas expression within a mean time of 68 months (p = 0.026). In conclusion, modulations of Fas and FasL expression are frequent events in esophageal carcinoma. Furthermore, downregulation of Fas seems to play a role in tumor cell dissemination and/or establishment of metastases in secondary organs via mediation of apoptotic resistance.