NERVE GROWTH-FACTOR SUPPRESSES THE TRANSFORMING PHENOTYPE OF HUMAN PROLACTINOMAS

The most effective therapy of human prolactinomas is represented by do pamine D-2 receptor agonists; there is, however, a population of nonre sponder patients who require surgical intervention. In the present stu dy, we report that prolactinomas totally resistant to pharmacological therapy have a high potential of both growing in soft agar and forming tumors in nude mice and lack D-2 receptors for dopamine. These tumors express the receptors for nerve growth factor (NGF) and are sensitive to its differentiating activity. After exposure to NGF for 4 days, pr olactinoma cells decreased their proliferation rate, lost their capabi lity to form colonies in soft agar, lost their tumorigenic activity in nude mice, and reexpressed the lactotroph-specific D-2 receptor prote in inhibiting prolactin release. These effects were permanent after NG F withdrawal and were reproducible in vivo in nude mice transplanted w ith the tumors. NGF in fact remarkably and lastingly depressed tumor g rowth and induced expression of D-2 receptors when injected intravenou sly once a day for 5 days into prolactinoma-bearing nude mice. These d ata suggest that NGF may induce a long-lasting switch of gene expressi on in human prolactinomas, modifying their transforming phenotype and reverting them to more differentiated, less malignant, dopamine-sensit ive lactotroph-like cells. The possibility thus arises that short-term treatment with NGF may restore the refractory patients to conventiona l pharmacological therapy with D-2 agonists.