Fas (APO-1, CD95) receptor expression and new options for immunotherapy inchildhood medulloblastomas

Central nervous system (CNS) tumors are the most common solid neoplasms in children. Medulloblastomas (MEDs) resemble embryonic neuroectodermal stem c ells and their immature, uncommitted neuronal and glial progeny. Apoptosis is a basic physiological process wherein the cell initiates a sequence of e vents culminating in the fragmentation of its DNA, nuclear collapse, and fi nally, disintegration of the cell into small, membrane-bound apoptotic bodi es. Expression of Fas (APO-1, CD95) receptor (FasR) and programmed ol activ e cell death (PCD) was studied in childhood MEDs with varying stages of mal ignancy, and cell differentiation features. The majority of neoplastically transformed neuroectodermal in origin cells, particularly in MEDs, express FasR, whereas normal cells in the CNS do not. FasR is a transmembrane glyco protein, which belongs to the nerve growth factor/tumor necrosis factor (NG F/TNF) receptor superfamily. Apoptosis within childhood PNETs/MEDs is trigg ered by the binding of FasR to ifs natural ligand (FasL) or. by cross-linki ng with anti- i FasR antibodies. The resence of FasL has also been detected in childhood glial tumors. Therefore, a spontaneous, cellular immunophenot ype (IP) regulatory, intratumoral apoptotic cell death (autocrine suicide) is possible in childhood brain tumors during neoplastic growth and progress ion. During our systematic immunocytochemical screening, we employed formal in fixed, paraffin-wax embedded tissue sections, as well as frozen sections of 34 primary human childhood PNETs/MEDs. The use of a sensitive, indirect , six step immunoperoxidase or alkaline phosphatase conjugated streptavidin -biotin antigen detection technique, modified by us, provided excellent imm unocytochemical results. A systematic observation of the presence of apopto sis related markers (especially FasR) and cells in PCD was carried out. A s trong expression (intensity of staining: "A"-the highest possible; number o f stained neoplastic cells: +++ to ++++, between 50% to 90%) of FasR, was d etected employing 4 mu m thick, formalin fixed, paraffin-wax embedded tissu e slides. The panel of normal tissues employed as positive and negative tis sue controls demonstrated presence of FasR in the prenatal thymus, mature t onsils and colon epithelium. Certainly, the coexpression of FasR, FasL, and other PCD-related proteins have also been reported in other human malignan cies: breast cancel; colorectal carcinomas, large granular lymphocytic leuk emia of T or NK cell origin melanomas, lung, prostate, pancreas, and hepato cellular carcinomas. The coexpression of both FasR and FasL on several neop lastic cell types may represent an effective mechanism for tumor escape of the cellular immunological response of the host. It has been well establish ed that brain tumors and melanomas produce their autocrine FasL, and even b ecome capable of switching their signal transduction from the PCD pathway t o a tumor growth, proliferative pathway. It seems that the therapeutical us e of FasR-FasL (main apoptotic pathway) represents a new and exciting immun otherapeutical possibility in the treatment of primary childhood neuroectod ermal tumors.