Predominant Expression of Fas (CD95) Ligand in Metastatic Melanoma Revealed by Longitudinal Analysis

Abstract

The expression of Fas ligand has recently been proposed as a novel tumor escape mechanism for melanoma. To establish the characteristics of Fas ligand expression during the course of melanoma progression we performed a longitudinal study analyzing primary tumors as well as subsequently evolving metastases. In primary melanoma Fas ligand was expressed in two of 20 lesions; this expression was weak and restricted to few parts of the tumors. The Fas ligand positive primary melanomas were rather thick, i.e., 8.5 and 3.8 mm, versus a median of 2.4 mm of the remaining tumors. In contrast, for metastatic melanoma Fas ligand expression was present in six of 11 cases investigated. The metastases of primary tumors displaying Fas ligand maintained its expression. As Fas ligand positive melanoma cells are capable of inducing apoptosis in susceptible cells, e.g., Fas positive tumor infiltrating lymphocytes, we tested for the presence of apoptotic cells in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. This analysis revealed that apoptotic cells were present within the Fas ligand positive tumors. The number of apoptotic cells, however, never exceeded 5% of the total cells. Thus, Fas ligand mediated apoptosis does not seem to be a major immune escape mechanism for melanoma but its expression correlates with the stage of melanoma.

Fas-Mediated Apoptosis of Melanoma Cells and Infiltrating Lymphocytes in Human Malignant Melanomas

“…The major finding of our study was that Fas expression in melanoma cells correlated significantly with the frequency of apoptosis of melanoma cells and that apoptosis of melanoma cells affected the prognosis of melanoma patients. We also found that both melanoma cells and infiltrating lymphocytes can express Fas and FasL in clinical specimens, extending the earlier findings that Fas is expressed in infiltrating lymphocytes (21) and FasL is expressed in melanoma cells (21)(22)(23)(24), though the lymphocyte apoptosis in itself was not significantly related to the prognosis. Therefore, these results indicate that the melanoma cell apoptosis mediated by the Fas-FasL system may affect the growth of melanoma and the prognosis of melanoma patients.…”

“…Recently, investigation of apoptosis of Faspositive lymphocytes induced by FasL-expressing tumor cells has been focused on tumor escape from immunological rejection in various malignant neoplasms, including hepatocellular carcinoma (7), colon cancer (18,35), and melanoma (21,23,24). Hahne (21) reported that FasL-expressing melanoma cells and Fas-positive lymphocytes were found in metastatic melanoma lesions.…”

“…Maeda et al (22) also found that human melanoma cells expressed FasL in primary lesions, whereas there was no expression of FasL in melanocytic nevus cells and normal melanocytes. More recently, it has been reported that FasL-positive melanoma cells and TUNEL-positive lymphocytes were found in primary lesions of human melanomas (23,24). It is possible that melanoma cells may induce apoptosis of lymphocytes mediated by Fas system.…”

“…It is possible that melanoma cells may induce apoptosis of lymphocytes mediated by Fas system. Furthermore, the expression of FasL on melanoma cells in metastatic lesions was correlated to the stages of melanomas (24). However, our knowledge of Fas expression in melanoma cells and of the interaction between melanoma cells and infiltrating lymphocytes in primary human malignant melanomas is still limited.…”

Protein-based therapeutic approaches targeting death receptors

“…Fas expression at the cell surface is observed in cell lines derived from a variety of tumors, including glioma, colon carcinoma, breast carcinoma, prostate cancer, neuroblastoma, melanoma and medulloblastoma. [24][25][26][27][28][29][30] Immunohistochemical studies have confirmed that such expression can be observed in tumors in vivo, or on freshly isolated tumor cells ex vivo. Cytotoxic drugs and tumor cell p53 status are known to have an influence on Fas-mediated apoptosis.…”