Nerve growth factor suppresses the transforming phenotype of human prolactinomas.

Abstract

The most effective therapy of human prolactinomas is represented by dopamine D-2 receptor agonists; there is, however, a population of nonresponder patients who require surgical intervention. In the present study, 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, prolactinoma cells decreased their proliferation rate, lost their capability to form colonies in soft agar, lost their tumorigenic activity in nude mice, and reexpressed the lactotroph-specific D-2 receptor protein inhibiting prolactin release. These effects were permanent after NGF withdrawal and were reproducible in vivo in nude mice transplanted with the tumors. NGF in fact remarkably and lastingly depressed tumor growth and induced expression of D-2 receptors when injected intravenously once a day for 5 days into prolactinoma-bearing nude mice. These data suggest that NGF may induce a long-lasting switch of gene expression in human prolactinomas, modifying their transforming phenotype and reverting them to more differentiated, less malignant, dopamine-sensitive lactotroph-like cells. The possibility thus arises that short-term treatment with NGF may restore the refractory patients to conventional pharmacological therapy with D-2 agonists.Nerve growth factor (NGF) is a neurotrophic protein that promotes the growth, differentiation, and survival of peripheral sympathetic neurons, the majority of neural crestderived sensory nerve cells (1-3), and the ascending cholinergic neurons ofthe basal forebrain (4)(5)(6). NGF also converts the pheochromocytoma cell line PC-12 into a sympathetic neuronal phenotype (7,8) and exerts a differentiating action on cells of the immune system (9, 10). The effects of NGF are directly dependent on initial binding to specific cell-surface receptors. Two protein components are required to form the high-affinity ligand-binding site for NGF: the 140-kDa protein-tyrosine kinase, which is encoded by the trkA protooncogene (gpl40trk) (11-13), and the 75-kDa glycoprotein gp75NGFR (14,15 We report here that bromocriptine-resistant prolactinomas lack D-2 receptors. Since these tumors express NGF receptors, we investigated whether they were sensitive to the differentiating action of the neurotrophic factor. The results show that exposure of prolactinoma cells to NGF resulted in their conversion into a more differentiated lactotroph-like phenotype reexpressing the D-2 receptor protein. MATERIALS AND METHODS Preparation of Prolactinoma Cell Cultures and Treatmentwith NGF. Tumor specimens were obtained from eight patients refractory to bromocriptine and five sensitive subjects who did not tolerate the drug. The five sensitive subjects responded to bromocriptine at 5-10 mg/day with a normalization of plasma PRL levels. Three of them were for...

Effect of a submaxillary gland extract on Ehrlich tumor growth in mice

“…In fact, this view is supported by the intra-nuclear immunohistochemical staining for NGF in Ehrlich tumor cells observed in previous studies (11). Tumor regression with NGF super-stimulation has been previously reported in human prolactinomas (12). In addition, tumor growth inhibition by NGF was observed also in rat T9 anaplastic glioma cells, in a dose-dependent manner, and was attributable to a gradual accumulation of growth-arrested cells at the G1 phase (13).…”

Nerve growth factor and bromocriptine: a sequential therapy for human bromocriptine-resistant prolactinomas

“…In a recent study with human prolactinomas we found that the tumours clinically resistant to bromocriptine do not express D-2 receptors for DA (Missale et al, 1993). However, these tumours do express receptors for nerve growth factor (NGF), a neurotrophic protein that promotes growth, differentiation and survival of specific populations of neurons (Levi-Montalcini, 1987) and that also exerts differentiating effects on cells of endocrine origin (Missale et al, 1994 15 ± 1 mm3, the mice were divided into four groups.…”

Growth factors and human pituitary adenomas

“…Moreover, the observation that mice overexpressing a pituitary-directed NGF transgene develop lactotroph hyperplasia suggest a proliferative action of this growth factor. A disruption of the NGF-mediated autocrine loop has been proposed to play a role in the development and progression of human prolactinomas (7). In fact, contrary to what has been observed in other pituitary tumors, prolactinomas removed from patients resistant to bromocriptine treatment seem to be unable to produce and release NGF in vitro.…”

“…Several experimental models indicate a permissive role for NGF in promoting development and maintenance of the lactotroph phenotype. In particular, NGF cooperates with EGF and bFGF in directing differentiation of lactotrophs by stimulating PRL synthesis and D2 dopaminergic receptor expression (7). Moreover, the observation that mice overexpressing a pituitary-directed NGF transgene develop lactotroph hyperplasia suggest a proliferative action of this growth factor.…”