NERVE GROWTH-FACTOR CONTROLS PROLIFERATION AND PROGRESSION OF HUMAN PROLACTINOMA CELL-LINES THROUGH AN AUTOCRINE MECHANISM

Two different human prolactinoma phenotypes (responders and nonrespond ers), which are distinguished by different tumorigenic potential and d ifferent responsiveness to dopaminergic therapy, have recently been id entified. Responders show low proliferation rate, low tumorigenic pote ntial, and expression of D-2 receptors for dopamine (DA), while nonres ponders are characterized by high proliferation rate, high tumorigenic potential, and lack of expression of DA D-2 receptors. In this study it has been shown that both gp140trk and gp75 components of nerve grow th factor (NGF) receptor are expressed in responder prolactinoma cell lines. High levels of both NGF gene transcript and protein were also f ound in responders, and biologically active NGF was detectable in the media conditioned by these cells. Ablation of NGF production in respon der cells by hybridization arrest of translation through NGF antisense oligonucleotides resulted in: 1) loss of secreted NGF; 2) loss of exp ression of gp75; 3) loss of expression of DA D-2 receptors; and 4) a r emarkable increase in the cell proliferation rate. These results thus suggest that a NGF-mediated autocrine loop essential to control cell p roliferation and to preserve some phenotypical characteristics of mamm otroph cells is present in responder prolactinoma cell lines. Analysis of nonresponders showed that these cells express gp140trk but no dete ctable levels of gp75. In addition, no NGF mRNA or protein was detecta ble in nonresponders. Exposure of these cells to NGF resulted in the p ermanent expression of NGF mRNA and in the production and secretion of NGF protein, thus establishing the same NGF-mediated autocrine loop p resent in responders. As a result, it has been shown that nonresponder cells treated with NGF acquire and maintain most of the phenotypic ch aracteristics of normal mammotroph cells. In conclusion, the present w ork reports that a NGF-mediated autocrine loop with an inhibitory role in the control of cell proliferation and tumor progression is active in the more differentiated DA-sensitive prolactinoma cell lines and is lost in the most malignant prolactinoma cells refractory to the dopam inergic therapy. Alterations in the expression of this autocrine loop thus may lead to cell transformation and tumor progression.