INCREASED RETINOIC ACID RECEPTOR-GAMMA EXPRESSION SUPPRESSES THE MALIGNANT PHENOTYPE AND ALTERS THE DIFFERENTIATION POTENTIAL OF HUMAN NEUROBLASTOMA-CELLS

Human neuroblastoma (NB) tumor cell lines treated in vitro with the re tinoid, all-trans-retinoic acid (aRA), form neurites and undergo growt h arrest, Retinoids exert their diverse morphologic effects through a signalling pathway which involves the nuclear retinoid receptors, Defe ctive retinoic acid receptor (RAR) function contributes to the maligna nt phenotype of several human and experimental tumors. Considerable ev idence from gene disruption studies now suggests that one of the RARs, RAR gamma, may directly mediate some retinoid effects on embryonic an d malignant cells. We, firstly, examined primary NE tumor tissue for a correlation between endogenous RAR gamma expression and clinical stag e of the tumor and secondly, the effects of exogenous overexpression o f the RAR gamma gene on a human NE tumor cell line. RAR gamma mRNA exp ression in 32 primary NE tumor tissue samples were significantly highe r in clinically localised tumors compared with advanced or disseminate d tumors. The human NE tumor cell line, BE(2)-C, was stably transfecte d with a mammalian expression (pREP4) over-expressing the human RAR ga mma cDNA. Two selected clones over-expressing RAR gamma and 2) exhibit ed a reduced growth rate compared to control cells, Tumorigenicity was inhibited for BE/G1 cells and there was a delayed onset to tumor form ation for BE/G2, cells. aRA caused growth inhibition but not neuritic differentiation of the BE/G clones, while 9-cis-retinoic acid caused b oth growth arrest and neuritic differentiation. Taken together these r esults suggest that reduced endogenous RAR gamma expression may contri bute to the malignant phenotype of human NE. In NE cells the retinoid signalling pathway for neuritic differentiation may be distinct from t hat causing growth inhibition.