title: Involvement of the Fas/FasL pathway in the pathogenesis of germ cell tumours of the adult testis.
abstract: Induction of apoptosis by Fas ligand (FasL) of Fas-containing cells is a known mechanism involved in the eradication of inappropriate cells during normal development. Alterations of the Fas/FasL pathway have been found in various types of cancer, leading to circumvention of attack of the tumour by the immune system. An alternative way to circumvent eradication by induction of apoptosis is through changes in the downstream inhibitors. For example, Fas-associating phosphatase-1 (Fap-1) binds directly to the Fas receptor and results in a block of the downstream signalling. To shed more light on the role of the Fas/FasL pathway in the development of human testicular germ cell tumours of the adult testis, this study investigated the presence of Fas, FasL, Fap-1, HLA class I and II molecules, CD45 (lymphocyte marker), and CD57 [natural killer (NK) cell marker] by immunohistochemistry on frozen sections of 41 cases of seminomas, non-seminomas, and spermatocytic seminomas. Every germ cell tumour was positive for Fap-1 and negative for HLA classes I and II, like their non-malignant cells of origin. The infiltrating lymphocytes, predominantly present in seminomas, showed consistently positive staining for Fas and CD45, but not for Fap-1. No Fas was found on NK cells. All seminomas and non-seminomas (except teratomas), including their precursor stages, carcinoma in situ, intratubular seminoma and intratubular non-seminoma, showed positive staining for FasL, but not for Fas. Teratoma showed no staining for FasL and was positive for Fas. In contrast, both Fas and FasL were detectable on spermatocytic seminoma. These data indicate a different regulation of the Fas/FasL system in seminoma and spermatocytic seminoma, supporting a separate pathogenesis for these germ cell-derived tumours. The presence of Fap-1 in all histological variants of germ cell tumours might be related to the consistently positive staining in cells of the germ lineage. This study indicates that production of FasL by the germ cell tumour cells might be involved in the early development of these types of adult testicular cancer by inducting apoptosis of Fas-positive, Fap-1-negative tumour-infiltrating lymphocytes.
authors.affiliation: Pathology/Laboratory for Exp. Patho-Oncology, University Hospital Rotterdam/Daniel, Josephine Nefkens Institute, Erasmus University Rotterdam, Building Be, Room 430B, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Anne-Marie F
authors.initials: AM
authors.lastname: Kersemaekers
authors.forename: Pascale C
authors.initials: PC
authors.lastname: van Weeren
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000328:Adult; D017209:Apoptosis; D053222:Fas Ligand Protein; D006681:HLA-D Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009373:Neoplasms, Germ Cell and Embryonal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018239:Seminoma / Q000209:etiology / Q000378:metabolism; D013736:Testicular Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019014:fas Receptor